viruses

Review
COVID-19 Vaccines for HIV-Infected Patients
Maria M. Plummer 1 and Charles S. Pavia 2,3, *

1 Department of Clinical Specialties, Division of Pathology, New York Institute of Technology,

NYIT College of Osteopathic Medicine, Old Westbury, NY 11568, USA; [email protected]
2 Department of Biomedical Sciences, New York Institute of Technology,
NYIT College of Osteopathic Medicine, Old Westbury, NY 11568, USA
3 Division of Infectious Diseases, New York Medical College, Valhalla, NY 10595, USA
* Correspondence: [email protected]; Tel.: +1-516-686-3778

Abstract: Nearly 40 years have passed since the initial cases of infection with the human mmunodefi-
ciency virus (HIV) were identified as a new disease entity and the cause of acquired immunodeficiency
disease (AIDS). This virus, unlike any other, is capable of causing severe suppression of our adaptive
immune defense mechanisms by directly infecting and destroying helper T cells leading to increased
susceptibility to a wide variety of microbial pathogens, especially those considered to be intracellular
or opportunistic. After T cells are infected, HIV reproduces itself via a somewhat unique mechanism
involving various metabolic steps, which includes the use of a reverse transcriptase enzyme that
enables the viral RNA to produce copies of its complementary DNA. Subsequent physiologic steps
lead to the production of new virus progeny and the eventual death of the invaded T cell. Fortu-
nately, both serologic and molecular tests (such as PCR) can be used to confirm the diagnosis of an
HIV infection. In the wake of the current COVID-19 pandemic, it appears that people living with
HIV/AIDS are equally or slightly more susceptible to the etiologic agent, SARS-CoV-2, than the
general population having intact immune systems, but they may have more serious outcomes. Lim-
ited clinical trials have also shown that the currently available COVID-19 vaccines are both safe and





 effective in affording protection to HIV/AIDS patients. In this review, we further explore the unique
dynamic of HIV/AIDS in the context of the worldwide COVID-19 pandemic and the implementation
Citation: Plummer, M.M.; Pavia, C.S.
of vaccines as a protective measure against COVID-19, as well as what immune parameters and
COVID-19 Vaccines for HIV-Infected
safeguards should be monitored in this immunocompromised group following vaccination.
Patients. Viruses 2021, 13, 1890.
https://doi.org/10.3390/v13101890
Keywords: HIV; AIDS; SARS-Cov-2; COVID-19; SARS-Cov-2 vaccines; mRNA
Academic Editor: Herve J. A. Fleury

Received: 7 July 2021

Accepted: 10 September 2021 1. Introduction and Historical and Epidemiologic Background
Published: 22 September 2021 When the acquired immunodeficiency syndrome (AIDS) was first described in 1981
and subsequently shown, two years later, to be caused by a previously unrecognized
Publisher’s Note: MDPI stays neutral pathogen, human immunodeficiency virus (HIV), it was believed to be confined to a small
with regard to jurisdictional claims in number of risk groups that were primarily gender-based and who were of a particular
published maps and institutional affil- sexual orientation or ethnicity [1]. As more information became known about the epi-
iations. demiologic picture of HIV transmission, it became clear that the infection was transmitted
primarily through sexual contact and exposure to blood either from the infusion of a con-
taminated blood product or through injection-drug use, as well as perinatally either from
the expectant mother to the fetus or during parturition, or via breast milk [2]. With the
Copyright: © 2021 by the authors. passage of time, it eventually became clear that susceptibility to HIV infection had crept
Licensee MDPI, Basel, Switzerland. into many parts of the general population having spread beyond the originally identified
This article is an open access article risk groups. In the United States, HIV type 1 (HIV-1) is the predominant strain, whereas
distributed under the terms and HIV type 2 (HIV-2) is prevalent elsewhere (e.g., in certain parts of West Africa) [3].
conditions of the Creative Commons In 2018, approximately 38,000 new cases of HIV infection were diagnosed in the
Attribution (CC BY) license (https://
United States and its territories [3]. Although perinatal transmission in the United States
creativecommons.org/licenses/by/
has decreased to very low levels owing to routine screening for HIV and initiation of
4.0/).

Viruses 2021, 13, 1890. https://doi.org/10.3390/v13101890 https://www.mdpi.com/journal/viruses

Viruses 2021, 13, 1890 2 of 16

antiretroviral therapy (ART) in HIV-infected women during pregnancy, cases in adoles-

cents and adults have decreased by only 7% between 2014 and 2018 [4]. Since the 1980s,
the populations most affected by HIV infection have changed, and this affliction is now
diagnosed disproportionately in persons who are impoverished, disadvantaged, and do
not have regular access to routine or high-quality medical care. In 2018, 21% of new HIV
infections were diagnosed in young people, 69% were diagnosed in men who have sex
with men, 10% in injection-drug users, 42% in Africa-Americans, and 27% in persons of
Hispanic or Latino ethnicities [3]. Around 25% of all new cases occur in white-skinned
persons, who comprise about 73% of the U.S. population.
An estimated 14% of persons with HIV infection in the United States is unaware of
having been exposed and of currently undergoing an active infection [3]. Many persons
at greater risk—in particular large segments of racial and ethnic minorities—have limited
access to skilled health care providers, and therefore, often a diagnosis is delayed until they
present with advanced disease, when treatments may be less effective and the risk of death
is highest [5].
In 2019, the United States began a program called the “Ending the HIV Epidemic”
plan with a goal of reducing the number of new infections by 75% by 2025 and by 90%
by 2030 [6]. The plan consists of four components: (i) to identify all persons with HIV
infection, preferably early on in the infectious process; (ii) to successfully treat them with
ART; (iii) to promote preventive measures against the development of new infections; and
(iv) to initiate a quick response to unforeseen outbreaks when they occur. The basis for the
first two components includes decreasing the gaps in early diagnoses, maintaining linkages
to care, rapid initiation of treatment in patients with HIV infection, and maintenance
of viral suppression by sustaining successful retention in patient compliance with the
designated treatment regimen. It is worth noting that a more comprehensive review on
the epidemiologic, clinical, diagnostic, and treatment related aspects of HIV/AIDS has
recently been published [7].

2. Human Immunodeficiency Virus (HIV) Pathogenesis

HIV is a retrovirus that causes severe immunosuppression and leads to opportunistic
infections, secondary neoplasms, and neurological abnormalities. Major transmission
routes include sexual contact, parenteral transmission (IV drug users, transfusion recipi-
ents), and mother to newborn (in utero via transplacental spread, during delivery, and via
breast milk).
There are two forms of HIV, HIV-1 and HIV-2, the former being the most common
type in the United States, Europe, and Central Africa, and the latter present mostly in West
Africa and India [7].

2.1. Structure of the Virus

HIV-1 has a spherical structure with an electron-dense, cone-shaped core surrounded
by a lipid envelope which comes from the host cell membrane after progeny viruses emerge
from an infected and now killed target cell. The virus core is made up of the major capsid
protein p24 (most abundant viral antigen), the nucleocapsid protein p7/p9, two copies of
viral genomic RNA, and three viral enzymes (protease, reverse transcriptase, and integrase).
The viral core is surrounded by a matrix protein known as p17, lying underneath the virion
envelope. The viral envelope is studded with two viral glycoproteins, gp120 and gp41,
essential for HIV infection of cells [8]. The HIV-1 RNA genome contains the gag, pol, and
env genes, which are common to retroviruses. The products of the gag and pol genes are
large precursor proteins cleaved by the viral protease, which then results in the mature
proteins being produced. HIV also contains other accessory genes, including tat, rev, vif,
nef, vpr, and vpu, which regulate the synthesis and assembly of infectious viral particles
and the pathogenicity of HIV [8].
Viruses 2021, 13, 1890 3 of 16

2.2. Pathogenesis
HIV infection mainly targets the immune system, though many other tissues can
be affected, including the central nervous system. AIDS, which results from HIV, causes
severe immunodeficiency, mostly affecting cell-mediated immunity, via infection and death
of CD4+ T cells and impairment in the function of surviving helper T cells. Infection of
macrophages and dendritic cells also occurs [8]. HIV enters the body via mucosal tissues
and blood and initially infects T cells as well as dendritic cells and macrophages. It becomes
established in lymphoid tissues of the body and may remain latent for a long period of
time, which is variable.

2.3. Life Cycle of HIV

The life cycle of HIV consists of infection of the aforementioned cells, integration of
the provirus into the host cell genome, activation of viral replication, and production and
release of infectious virus progeny. HIV infects cells via the CD4 molecule as a receptor and
other chemokine receptors (coreceptors). However, this binding to CD4 is not enough for
infection. HIVgp120 also needs to bind to other coreceptors for entry into the cell, especially
CCR5 and CXCR4 [8,9]. Different HIV isolates are recognized by their use of these receptors:
R5 strains use CCR5 and X4 strains use CXCR4. Some strains such as R5X4 use both. R5
strains are usually M-tropic, meaning they infect cells of the monocyte/macrophage lineage
in addition to T cells. X4 strains are T-tropic, mostly infecting T cells. In about 90% of cases,
the R5 (M-tropic) type of HIV is the dominant virus in acutely infected people’s blood, early
in the infection. As the infection progresses, T-tropic viruses slowly accumulate, which are
especially virulent because they can infect many T cells and even thymic T cell precursors,
causing more impairment and loss of T cells [9,10].
The HIV envelope has two noncovalently associated glycoproteins, surface gp120 and
gp41, the transmembrane protein. The first step in infection is binding of surface gp120
to CD4. This causes a conformational change producing a new recognition site on gp120
for the coreceptors CCR5 or CXCR4. Binding to the coreceptors causes conformational
changes in gp41 so that a hydrophobic region known as the fusion peptide is exposed at
the tip of gp41. This peptide inserts itself into the cell membrane of the target cells (e.g.,
T cells or macrophages), which leads to fusion of the virus and the host cell membrane,
allowing the virus core, which contains the HIV genome, to enter the cell [9,10].
The need for HIV binding to coreceptors may be important in the pathogenesis of
AIDS. Chemokines hinder HIV infection of cells in culture by occupying their receptors,
and so, the chemokine levels in tissue may influence viral infection efficiency in vivo. In
addition, polymorphisms in the gene encoding CCR5 are associated with different HIV
infection susceptibility. About 1% of white-skinned Americans inherit two mutant copies
of the CCR5 gene and are resistant to infection and the development of AIDS associated
with R5 HIV isolates. About 20% of people are heterozygous, and though not protected
from AIDS, these individuals tend to progress to AIDS later on [11,12].
Once inside the host cell, the RNA genome of HIV undergoes reverse transcription,
which leads to synthesis of double-stranded complementary DNA (cDNA). In dividing
T cells, the cDNA circularizes, enters the nucleus, and integrates into the host genome.
After integration, the provirus may be latent for months or years, or proviral DNA may
be transcribed resulting in formation of complete viral particles that bud from the cell
membrane. When there is extensive budding, the infected cells die [11]. HIV infects
memory and activated T cells but is not efficient at productively infecting naïve (resting) T
cells because these cells have an enzyme that introduces a mutation in the HIV genome.
This enzyme is apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G. It
is a cytidine deaminase that introduces cytosine-to-uracil mutations in the viral DNA that
are produced by reverse transcription. However, HIV has evolved to escape this defense.
The viral protein Vif binds to the enzyme and causes it to degrade via cellular proteases.
The viral life cycle is completed in latently infected cells only after cell activation, and for
most CD4+ T cells, viral replication and shedding result in cell lysis. Activation of T cells
Viruses 2021, 13, 1890 4 of 16

by antigens or cytokines upregulates transcription factors, including NF-κB, that stimulate

transcription of genes that encode cytokines such as IL-2 and its receptor [11]. In resting T
cells, NF-κB is inactive in the cytoplasm because it is complexed with the IκB (inhibitor of
κB) protein. Stimulation of cells by antigen or cytokines activates cytoplasmic kinases that
phosphorylate IκB, targeting it for enzymatic degradation. This releases NF-κB and allows
it to translocate to the nucleus. In the nucleus, NF-κB binds to the regulatory sequences
of several genes, including those encoding for various of cytokines that are expressed in
activated T cells.
The long-terminal-repeat sequences that flank the HIV genome also contain NF-κB-
binding sites that can drive the expression of viral RNA. In addition, TNF and other
cytokines produced by activated macrophages stimulate NF-κB activity in T cells. HIV
appears to thrive when the host T cells and macrophages are physiologically activated.
This activation in vivo may result from antigenic stimulation by HIV itself or by other
infecting microorganisms. HIV-infected people are at increased risk for other infections,
which lead to increased lymphocyte activation and production of proinflammatory cy-
tokines. These then stimulate more HIV production, loss of additional CD4+ T cells, and
more infection [11,12]. The infected CD4+ T cells are lost mostly because of the direct
cytopathic effects of the replicating virus. Of note, many infected cells are within tissues
(e.g., secondary lymphoid organs and mucosal sites), and death of these cells is a major
cause of the extreme cell loss. As the disease progresses, renewal of CD4+ T cells cannot
keep up with their loss.
Not only is there direct killing of cells by the virus, but the loss of T cells may also occur
via other mechanisms. These include chronic activation of uninfected cells which leads
to apoptosis of these cells so that the number of CD4+ cells that die may be much more
than those infected. In addition, noncytopathic HIV infection activates the inflammasome
pathway, leading to cell death via pyroptosis in which inflammatory cytokines and cell
contents are released which can recruit new cells and increase the number of infected cells.
HIV also infects cells in secondary lymphoid organs such as the spleen, lymph nodes,
and tonsils, which may cause more destruction of the architecture and cellular make-up
of lymphoid cells. Immature precursors of CD4+ T cells can also be lost either by direct
infection of thymic progenitor cells or by infection of cells that secrete cytokines needed
for CD4+ T cells to mature. Another way T cell loss can occur is via fusion of infected and
uninfected cells with formation of giant cells. Fused cells die within a few hours. This
usually occurs in the T-tropic X4 type of HIV-1, referred to as syncytia-inducing virus [11,12].
The severe reduction in CD4+ T cells can account for most of the immunodeficiency late
in HIV infection. However, there is also evidence of qualitative defects in T cells even in
asymptomatic HIV-infected persons. These qualitative defects include reduced antigen-
induced T cell proliferation, decreased Th1-type responses, and defects in intracellular
signaling, to name a few. The loss of Th1 responses results in a severe deficiency of cell-
mediated immunity. This leads to increased susceptibility to infections by viruses and
other primarily intracellular microbes [8].
An important feature of HIV infection is low-level chronic or latent infection of T cells.
The integrated provirus, without viral gene expression (latent infection), can stay in the
cells for months to years. Even with antiviral therapy, latent virus remains within the CD4+
cells (both T cells and macrophages) in the lymph nodes. About 0.05% of CD4+ T cells in
the lymph nodes are latently infected, most of which are memory cells with a long life span.
This provides a reservoir for the virus [12].

2.4. HIV Infection of Non-T Cells

Also important in the pathogenesis of HIV infections is infection of macrophages and
dendritic cells. Just like in T cells, the number of HIV infected macrophages in tissues is
much greater than the number of infected monocytes in the blood. Some organs like the
lungs and brains may have up to 10% to 50% of infected macrophages [12]. HIV-1 can
infect and multiply in terminally differentiated nondividing macrophages. This depends
Viruses 2021, 13, 1890 5 of 16

on the viral vpr gene. The Vpr protein permits nuclear targeting of the HIV pre-integration
complex via the nuclear pore.
Infected macrophages bud small amounts of virus from the cell surface but contain
a large amount of virus particles, often in intracellular vesicles. Unlike CD4+ T cells,
macrophages are resistant to the cytopathic effects of HIV. Therefore, in late-stage HIV
infection when CD4+ T cells are greatly depleted, macrophages may be an important
site of continued viral replication and a viral reservoir. The reason why macrophages
may be important portals of infection is because, in more than 90% of cases, acute HIV
infection is caused by M-tropic strains [12]. Uninfected monocytes may also have unex-
plained functional defects including impaired microbicidal activity, decreased chemotaxis,
decreased secretion of IL-1, inappropriate secretion of TNF, and poor processing capability
needed to present antigens to T cells. In addition, infected monocytes may carry the virus
from the blood to other parts of the body, such as the nervous system, where it can infect
microglial cells. Two types of dendritic cells are also important in HIV infection: mucosal
and follicular dendritic cells. It is believed that mucosal dendritic cells are infected by HIV
and may transport it to regional lymph nodes, where HIV is transmitted to CD4+ T cells.
In addition, dendritic cells also have a lectin-like receptor that binds HIV and displays it in
an intact, infectious form to T cells, which promotes infection of T cells. Follicular dendritic
cells in the germinal centers of lymph nodes are potential reservoirs of HIV. Most virus
particles are present on the surface of their dendritic processes. Follicular dendritic cells
have receptors for the Fc portion of immunoglobulins. They can then trap HIV virions
coated with anti-HIV antibodies. These antibody-coated virions on the follicular dendritic
cells have the ability to infect CD4+ T cells. Infected T follicular helper cells in the germinal
centers are also reservoirs of HIV [12]. Because CD4+ T cells are needed in regulating both
cellular and humoral immune responses, this loss greatly affects the immune system.

2.5. HIV and B Cells

Although HIV infects T cells, macrophages, and dendritic cells, people with AIDs
also have abnormalities in B-cell function. Early in the disease process, there is polyclonal
activation of B cells, causing germinal center B-cell hyperplasia. B-cell activation may occur
via reactivation of, or reinfection with, Epstein Barr virus, which is a polyclonal B-cell acti-
vator; viral gp41 (which can promote B-cell growth and differentiation); and increased IL-6
production, which stimulates proliferation of B cells, by HIV-infected macrophages [9,12].
Despite the increased activation of B cells and risk of autoimmunity, patients with AIDS can-
not produce effective antibody responses. This may partly be because of lack of T-cell help
but apparently antibody responses against T-independent antigens are also suppressed, so
there may be intrinsic B cell defects. Furthermore, this impaired humoral immunity makes
patients susceptible to disseminated infections caused by encapsulated bacteria (e.g., Strep-
tococcus pneumoniae and Haemophilus influenzae), which need antibodies for opsonization
and clearance [8].

2.6. HIV and the Nervous System

The nervous system is also affected by HIV infection. Microglia in the CNS are the
main cell types infected with HIV. It is thought that infected T cells or monocytes carry
HIV into the brain though it is not certain how HIV induces damage. Because neurons
are not infected by HIV and neuropathologic changes are less than expected considering
the severity of neurologic symptoms, it is thought that the neurologic deficit is caused
indirectly by viral products and by soluble factors produced by infected microglia (e.g.,
IL-1, TNF, and IL-6). It is also thought that gp41 induces nitric oxide in neurons and that
direct damage of neurons by soluble HIV gp120 may occur [9,12].

2.7. HIV and Renal Disease

Another organ affected by HIV infection is the kidney. HIV-associated nephropathy
(HIVAN) is a leading cause of end stage renal disease in HIV-1 positive patients and may
Viruses 2021, 13, 1890 6 of 16

lead to death [13,14]. Classically, the clinical presentation of HIVAN involves progressive
azotemia, rapidly progressive renal failure, proteinuria ranging from moderate to nephrotic
range (though usually little to no peripheral edema), bland urinary sediment, and large,
highly echogenic kidneys based on ultrasound results [13,14].
In a study of 107 HIV infected patients who underwent kidney biopsy between 1995
and 2002, those who had classic HIVAN were also more likely to have a CD4 cell count
<200 cells/mm3 [14]. In autopsy studies, gross examination has revealed enlarged, pale,
swollen kidneys in patients with HIVAN [14]. Microscopically, there is renal parenchymal
injury showing epithelial cell proliferation, dedifferentiation, and apoptosis along the
nephron, with collapsing focal segmental glomerulosclerosis (FSGS), microcystic tubular
dilation, interstitial inflammation, and fibrosis [13]. Untreated HIVAN patients in the acute
phase usually show a dramatic pattern of collapsing FSGS with glomerular capillary lumina
occluded by wrinkling and collapse of the glomerular basement membrane [14]. This is
associated with prominent hypertrophy and hyperplasia of the overlying podocytes, show-
ing enlarged, open vesicular nuclei with frequent nucleoli, occasional binucleate forms, and
rare mitotic figures [14]. Pseudocrescents may form because of the very crowded visceral
epithelial cells that obliterate the urinary space. The cytoplasm of the podocytes is usually
vacuolated with prominent intracytoplasmic protein resorption (hyaline) droplets [14].
Over time, the glomerular tuft retracts into a tight, solid ball crowned by overlying enlarged,
vacuolated visceral epithelial cells.

2.8. HIV Infection Natural History

Acute (early) HIV infection is marked by infection of memory CD4+ T cells (which
express CCR5) in mucosal lymphoid tissues and leads to death of many infected cells.
Because the mucosal tissues are the largest reservoir of memory T cells in the body and
memory T cells are susceptible to HIV infection, this results in a great loss of lymphocytes.
Mucosal infection is often associated with damage to the epithelium, defects in mucosal
barrier functions, and translocation of other microbes across the epithelium [9]. After
mucosal infection, dissemination of the virus and development of host immune responses
occur. Dendritic cells in epithelia at virus entry sites capture the virus and then migrate
into the lymph nodes. Once there, the dendritic cells may pass HIV on to CD4+ T cells via
direct cell-to-cell contact. Viral replication can be detected in the lymph nodes within days
after the first exposure to HIV. This leads to viremia, so that high numbers of HIV particles
are present in the patient’s blood. The virus disseminates throughout the body and infects
helper T cells, macrophages, and dendritic cells in peripheral lymphoid tissues [9].
As the HIV infection spreads, antiviral humoral and cell-mediated immune responses
are produced by the patient. These lead to seroconversion (usually within 3 to 7 weeks
of exposure) and the development of virus-specific CD8+ cytotoxic T cells—one of the
remaining non-humoral immune system components not directly affected by the virus.
HIV-specific CD8+ T cells are detected in the blood around the same time viral titers
begin to fall and are most likely the cause of initial containment of HIV infection. These
immune responses partially control the infection and viral production. This is seen by a
drop in viremia to low but detectable levels by about 12 weeks after primary exposure [9].
The “acute retroviral syndrome” clinically reflects the initial spread of the virus and the
host response. About 40 to 90% of people who acquire a primary infection develop this
syndrome, which usually occurs 3 to 6 weeks after infection and resolves spontaneously
in the next 2 to 4 weeks. It is characterized by a nonspecific self-limited acute illness with
flu-like symptoms, such as sore throat, myalgias, fever, weight loss, and fatigue, sometimes
with a rash, cervical adenopathy, diarrhea, and vomiting [11].
Measuring the viral load or level of HIV-1 RNA in the blood is a useful way to monitor
HIV disease progression (refer to diagnosis below) and is helpful for clinical management,
especially in the course of the patient receiving antiretroviral treatment. However, the
blood CD4+ T-cell count is probably the most reliable short-term indicator of disease
Viruses 2021, 13, 1890 7 of 16

progression. Therefore, the CD4+ cell count (rather than viral load) is the primary clinical
measurement used to determine when to start antiretroviral therapy (ART) [7].

2.9. Chronic HIV Infection

In the chronic phase of HIV infection, the areas of continuous HIV replication and
cell destruction are the lymph nodes and spleen. During this period, there are few or
no clinical manifestations of the HIV infection, and this is known as the clinical latency
period. Although the majority of peripheral blood T cells do not have the virus, destruction
of CD4+ T cells within lymphoid tissues continues and the number of CD4+ T cells in
the blood continues to decline. Over a period of years, the slowly amplifying cycle of
virus infection, T cell death, and new infection results in a continued decline in CD4+
T cell numbers in the lymphoid tissues and peripheral circulation [9]. Along with this
loss of CD4+ T cells, host defenses decline, and the proportion of surviving CD4+ cells
infected with HIV increases, as well as the viral burden per CD4+ cell. HIV RNA levels
increase. Although not completely elucidated, HIV may escape immune control because
of destruction of the CD4+ T cells needed for effective immunity, antigenic variation, and
down-modulation of class I MHC molecules on infected cells so that viral antigens are
not recognized by CD8+ CTLs. During this period, the virus may evolve and switch from
only relying on CCR5 to enter its target cells to relying on either CXCR4 or both CCR5 and
CXCR4. This coreceptor switch is associated with more rapid decline in CD4+ T-cell counts,
because more T cells are infected. Patients in this chronic phase of infection are either
asymptomatic or develop certain types of opportunistic infections, such as oral candidiasis
(thrush), vaginal candidiasis, herpes zoster, and tuberculosis [8].

2.10. AIDS
The final phase of HIV infection is the development of AIDS with a breakdown of
host defenses, a great viral load increase, and profound, life-threatening clinical disease.
The typical person with AIDS presents with long-lasting fever (>1 month), fatigue, weight
loss, diarrhea, and generalized lymph node enlargement. After a period, which varies, a
wide range of serious opportunistic infections, secondary neoplasms, or clinical neurologic
disease may develop [7,8]. Without treatment, most patients with HIV infection progress to
AIDS after a chronic phase lasting from 7 to 10 years. However, some patients are rapid pro-
gressors or long-term nonprogressors. In the former group, the middle, chronic phase is 2
to 3 years after primary infection. About 5 to 15% of infected individuals are long-term non-
progressors, defined as untreated HIV-1-infected individuals who remain asymptomatic for
10 years or more, with stable CD4+ T-cell counts and low viral loads. There are even about
1% of infected individuals (elite controllers) who have undetectable plasma virus [12]. A
typical adult patient in the United States with AIDS presents with fever, weight loss, diar-
rhea, generalized lymphadenopathy, multiple opportunistic infections, neurologic disease,
and, in many cases, secondary neoplasms. Collectively, these clinical abnormalities include
pneumocystis pneumonia, toxoplasmal encephalitis, candidiasis, cryptococcal meningitis,
atypical mycobacterial infections, cytomegalovirus infection, Kaposi sarcoma, primary
lymphoma of the brain, and progressive multifocal leukoencephalopathy [8,12]. Ninety
percent of patients show some form of neurologic involvement at autopsy, and 40% to
60% have clinical neurologic dysfunction. With treatment, the mortality rate in the U.S.
has declined, over the past several years, but treated patients still carry viral DNA in their
lymphoid tissues. Molecular analyses show a lot of variation in viral isolates from patients,
which makes vaccine development difficult as a preventive measure against HIV infection.
There have been some recent efforts focusing on producing broadly neutralizing antibodies
against relatively invariant portions of HIV proteins [9].

2.11. Diagnosis of HIV/AIDS

Apart from the clinical presentation and an accurate medical history, several tests are
available to accurately diagnose or confirm an HIV infection (summarized in Figure 1).
 variation in viral isolates from patients, which makes vaccine development difficult as a
preventive measure against HIV infection. There have been some recent efforts focusing
on producing broadly neutralizing antibodies against relatively invariant portions of HIV
proteins [9].
Viruses 2021, 13, 1890 8 of 16
2.11. Diagnosis of HIV/AIDS
Apart from the clinical presentation and an accurate medical history, several tests are
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earliest one—the nucleic acid amplification test (NAT)—to the latest assay system (test for IgG an-the graph, from
the earliestAone—the
tibodies). Westernnucleic
blot (oracid amplification
immunoblot) testto
is used (NAT)—to
confirm an the latestpositive
initial assay system (test for
result from IgG
a stand-
antibodies). A Western blot (or immunoblot) is used to confirm an initial positive result from an
ard serologic test such as an ELISA. This latter aspect of the serologic algorithm is to ensure that a
initial serologically-derived
standard serologic test such aspositive
an ELISA.test result
This latterisaspect
not a of
false-positive.
the serologic A Westernisblot
algorithm is alsothat
to ensure not
supposed
an to be used initially as
initial serologically-derived a screening
positive test, irrespective
test result of the patient
is not a false-positive. presentation,
A Western blot isprimarily
also not
for cost-containment purposes. Adapted from Maag, 2021 [7].
supposed to be used initially as a screening test, irrespective of the patient presentation, primarily for
cost-containment purposes. Adapted from Maag, 2021 [7].

3. COVID-19 Pathogenesis
COVID-19 is caused by a unique virus called SARS-CoV-2. It belongs to the Coronoviri-
dae family of viruses [15] displaying a crown-like morphology with spike (S) glycoproteins
radiating from its surface [16]. All the coronaviruses are large, enveloped, single-stranded
RNA viruses that are found in humans and animals [17]. SARS-CoV-2 major structural
proteins include a spike surface glycoprotein (S), a small envelope protein (E), a matrix
Viruses 2021, 13, 1890 9 of 16

protein (M), and a nucleocapsid protein (N) [15]. The N protein forms as a helical capsid
to pack the genome, which is wrapped with an envelope consisting of the spike surface
glycoprotein (S), a small envelope protein (E), and a matrix protein (M) [15]. The S gly-
coprotein helps regulate binding of the receptors and the virus into host cells, and the
E protein and M protein are involved in virus assembly [13]. The S protein has three
segments—an ectodomain, a single-pass transmembrane anchor, and a short intracellular
tail. The ectodomain has a receptor-binding S1 domain and a membrane-fusion S2 domain,
which are very important for virus entrance into the host cells via receptor binding and
membrane fusion. The envelope is also important because it is involved in viral assembly
and the V-release process [15].
SARS-CoV-2, like other RNA viruses, has a great deal of genetic variability because
there is a lack of proof-reading activities of viral RNA-dependent polymerase, making it
more adaptable to survival [18]. There is variability of the amino acid sequences in the
spike protein for host cell receptor binding and the virus has the capability to evolve to be
more replication efficient. In addition, some of the viral proteins may evolve into mediators
that do not allow the host immune system to recognize or attack infected cells. The virus
may also be able to develop drug resistance [18].
COVID-19 is most commonly transmitted via contact with respiratory droplets from
talking, coughing, and sneezing during face-to-face exposure [15]. Direct inhalation of
infected particles and contact transmission via oral, nasal, and eye mucous are also im-
portant. The incubation period of the virus is thought to be usually 3–7 days but can be
up to two weeks, although 97.5% of individuals who do develop symptoms do so within
11.5 days of infection [17]. After being inhaled, SARS-CoV-2 enters the host cells first by
binding of the spike protein to the angiotensin converting enzyme (ACE)2 receptor on the
cells’ surfaces [16]. This receptor is found on many types of tissues in the body including
the lungs (especially type 2 pneumocytes in the alveoli), blood vessels, heart, liver, kidneys,
upper respiratory tract epithelium, and the gastrointestinal tract [16]. This helps explain
the frequency of pneumonia as well as vasculitis, the presence of fecal viral RNA and
antigen detection, as well as other organ disease manifestations [18]. After the binding of
virus to the ACE2 receptor on the host cell and subsequent entry into the cell, the virus
replicates, and in later stages, the viral load becomes higher causing compromise of the
epithelial-endothelial barrier [15]. Of note, smokers have an increased lung expression of
ACE2 receptors [18], which could exacerbate disease progression.
The host response includes elicited inflammation early on, which results in an in-
filtration of numerous monocytes and neutrophils to the target sites [17]. In addition,
inflammatory signaling molecules are released by infected cells, alveolar macrophages and
recruited monocytes, neutrophils, and T lymphocytes [18]. As the disease progresses, SARS-
CoV-2 virus infects pulmonary capillary endothelial cells, which also triggers an influx of
monocytes and neutrophils, killing T lymphocyte cells, further increasing the inflammatory
response. This results in a thickened interstitium, hyaline membrane formation, pulmonary
edema, and activation of coagulation factors, which can lead to microthrombi [16]. Viral
sepsis may develop, which further leads to multiorgan failure [18]. Therefore, it appears
that the viral infection causes an excessive immune response, with the key aspect being
what has come to be known as a “cytokine storm”—leading to critical illness and death due
to severe pneumonia and other systemic complications [17]. The interstitial mononuclear
inflammation and edema which develop in the lung are seen by computed tomographic
imaging as ground glass opacities [19]. The pulmonary findings can be divided into ear-
lier and later phases with earlier manifestations of pulmonary edema, protein exudation,
vascular congestion, pneumocyte hyperplasia, interstitial thickening, inflammation with
fibrinoid material and multinucleated giant cells, and hyaline membrane formation [15].
Later features include diffuse alveolar damage with fibrous mucus-like exudates, desqua-
mation of pneumocytes, and hyaline membrane formation (as found in acute respiratory
distress syndrome) [15].
Viruses 2021, 13, 1890 10 of 16

The first completed autopsy report of a deceased COVID-19 patient was released
in February 2020 and showed an extensive inflammatory reaction with deep airway and
alveolar damage [18]. Electron microscopy examination of autopsy specimens showed
large numbers of viral particles in alveolar epithelial cells [20]. Other postmortem studies
have shown that the lungs, especially the middle and lower lung lobes, were adherent to
the chest wall, implying inflammation of the peripheral lung tissue leading to the formation
of adhesions. Microscopically, the findings included the presence of diffuse alveolar wall
thickening with mononuclear cells and macrophages infiltrating the alveoli and endothe-
lialitis. Many patients also had secondary bacterial infections, while a few had secondary
fungal infections [18]. Other key postmortem findings from different studies have included
the presence of large amounts of chemokines coming from the macrophages in the bron-
choalveolar fluid (in severe disease), damage to the alveoli with interalveolar hemorrhage,
vascular congestion, and type 2 pneumocyte hyperplasia [19]. In addition, myocarditis
and cardiomyopathy, fibrin thrombi in alveolar arterioles, and microthrombi (indicating
coagulation problems) in the lungs, liver, brain, heart, lower limbs, hands, and kidneys
have been described. Neurological postmortem findings included hemorrhagic white
matter lesions throughout the cerebral hemispheres, axonal injury, clusters of macrophages,
and a perivascular acute disseminated encephalomyelitis-like appearance [19]. A more
recent systematic review and meta-analysis of postmortem findings that are associated
with COVID-19 was recently published [20], which showed that the most common cause
of mortality was diffuse alveolar damage. However, there were also other remarkable find-
ings, which included thromboembolism, brain infarction, endotheliitis, acute renal tubular
damage, white pulp depletion in the spleen, necrosis of cardiac myocytes, recruitment of
megakaryocytes, and hemophagocytosis [20].

Diagnosis of COVID-19
As soon as the COVID-19 pandemic began to emerge, the default “gold standard”
test, which diagnostic laboratories have relied on, and continue to rely on, was a nucleic
acid amplification test, most notably PCR, to detect people who have been infected with
SARS-CoV-2 [21–23]. As with most difficult-to-culture pathogens, PCR has replaced the
cumbersome and time-consuming in vitro culture of the virus from patient samples for
diagnostic purposes, although some versions may require several hours before results are
available, often depending upon the workload of the testing facility. The sensitivity and
specificity of this assay system is relatively high and assures quick and reliable identification
of infected persons who may go on to develop serious disease and potentially transmit the
virus unwittingly to others [22,23].
The next most reliable assay system for detecting COVID-19 is serology. The detection
of anti-SARS-CoV-2 antibodies is useful when PCR is not available for confirming suspi-
cious cases, or when PCR test results are repeatedly negative yet there is a high suspicion
of disease, or the patient presents late in disease when viral RNA may be very low or
absent from a patient sample, such as a nasal swab or blood. Owing to the high level
of serology’s sensitivity, antibodies appear relatively early (2–3 weeks of infection) [21]
and are directed against the spike and nucleocapsid antigens. An additional benefit of
serology is the identification of prospective donors of convalescent plasma for use in certain
treatment regimens [24].
Unfortunately, in many countries, especially those with weak health care systems or
infrastructure and/or limited laboratory capabilities, access to these two forms of testing
can be challenging and/or it is difficult to get timely results. As an alternative, antigen-
detection systems have been developed (reviewed in Reference [25]) which could alleviate
this problem. These tests are intended for the qualitative detection of key antigens, such
as the nucleocapsid protein, from SARS-CoV-2 in nasal swabs, from people suspected of
having contracted COVID-19 by their health-care provider, and similarly to PCR, such
results can be obtained within the first few hours or less of symptom onset. Patient samples
are tested immediately after being collected, and there is no need in some platforms to
Viruses 2021, 13, 1890 11 of 16

dilute the sample in any type of transport media or solution prior to applying the sample
onto the test device. These devices are relatively inexpensive and compact (about the size
of a credit card), can be purchased at most local pharmacies without a prescription, can
be performed outside the confines of a health care facility, and are capable of providing
results in approximately 15–30 min. In most cases, results can be read visually without the
need for any additional equipment or instrumentation. Unfortunately, while the sensitivity
of most of the currently available antigen-detection tests is excellent, their sensitivity has
been shown to vary from low to high [25]. A comparison of the various features, including
the performance characteristics of the three different detection systems, is shown below in
Table 1.

Table 1. Summary of some of the similarities and differences between molecular-based tests (for example, RT-PCR), serologic
assays and antigen-detection tests that are currently in use for the diagnosis of COVID-19.

RT-PCR Tests Serologic Assays Antigen Tests

Intended Use Detect current infection Detect current/past infection Detect current infection
Type of Analyte Detected Viral RNA Immunoglobulin(s) Viral antigens
Specimen Types(s) Nasal swab; Saliva Serum or plasma Nasal swab; saliva
Sensitivity High Moderate to high Low to moderately high
Sensitivity High Moderate to high High
Test Complexity Variable Variable Relatively easy to use
Authorized for use at the Most formats are not, some
Same as PCR Yes
point-of-care site formats are allowed
Turnaround time for a Ranges from about 15–30 min
Same as PCR About 15–30 min
test result to >2 days
Cost per test Moderate Moderate Low
Screening No No Yes
Confirmation Yes Yes No or yes
Persistence of analyte
No Yes a No
after recovery
a Detectable level of antibodies tend to decrease gradually over time with the major isotype being IgG. Adapted from Pavia and
Plummer [25].

4. COVID-19 Vaccines for the HIV-Infected Patient

The speed with which safe and effective vaccines have been developed to prevent
COVID-19 has been nothing short of remarkable and perhaps even spectacular. In just a few
months after the pandemic became recognized as a global nightmare and a sense of urgency
had crept into the picture, potential vaccines were produced by several manufacturers and
became available for testing. This outcome is a testament to the hard work and diligence of
the research community and pharmaceutical industry in cooperating in this venture, along
with the huge response of the general population willing to participate in clinical trials
that were needed to verify the worthiness of these vaccines. Even many of the recognized
medical/scientific “experts” had predicted that vaccines would likely not be available for
routine use for almost two years after the initiation of experiments to try to develop them.
Certainly, in the back of many minds was the gloomy feeling that it may even take much
longer given the relative lack of success, after much effort and a large amount of funds had
already been invested, over a span of many years, in trying to develop effective vaccines
for malaria, HIV infection, and EBOLA virus disease (EVD)—diseases having high rates
of morbidity and mortality (similar outcomes to COVID-19), but which have been known
and well characterized for well over a century (for malaria) and for nearly a half century
(for HIV infection and EVD).
Viruses 2021, 13, 1890 12 of 16

As of August 2021, two types of anti-COVID-19 vaccines are in use and available
to everyone from ages twelve and above. One type consists of purified messenger RNA
(mRNA) given in two intramuscular injections with the second injection given 3–4 weeks
after the first one. The mRNA encodes for the SARS-CoV-2 spike protein. The other
vaccine has a viral vector formulation with a live but safe adenovirus serving as the vector
for carrying the genome of the SARS-CoV-2 spike protein and only needs to be given
once in one of the two versions currently available (Table 2). In both cases, the spike
protein had been shown to be highly immunogenic and the key protective component
in pre-clinical studies and is associated with a vigorous antibody response. After an
initial Emergency Use Authorization (EUA) that was issued in December 2020 and then
followed by a second one in February 2021 by the U.S. Food and Drug Administration
(FDA), the two mRNA vaccines produced by Pfizer (Pearl River, NY, USA) and Moderna
(Cambridge, MA, USA) are pending final approval for routine use as of August 2021.
This is also true for the viral vector vaccines produced by Janssen/Johnson & Johnson
(Titusville, NJ) and Astra-Zeneca (Cambridge, UK), which have received an EUA for adults
(≥15 year’s old) in the U.S. It should be noted that in the United Kingdom much earlier
approval was given in December 2020 and January 2021, for some of these vaccines, by
the U.K. Health Department following recommendations by the Medicare and Health
Care Regulatory Authority in the Department of Health and Social Care. The key features
of these four vaccines are summarized in Table 2. It is worth noting that, from the very
beginning, the rapid deployment of these vaccines, especially in the U.S., was partially
aided by the involvement of the U.S. federal government under the program known as
“Operation Warp Speed” [26]. Although some people may have viewed this program
as being partially politically motivated, it provided considerable financial and logistical
support to the pharmaceutical industry for accelerating the development and distribution
of multiple vaccines throughout much of the U.S. in a nearly unprecedented fashion.

Table 2. Comparison of the key features of the COVID-19 vaccines that are produced by the four leading manufacturers.

Authorized for Use in Serious

Vaccine Type of Number of Emergency Use Percent
the U.S. a Pending Adverse
Manufacturer. Vaccine Doses Authorization b Efficacy
Final Approval Events
Moderna mRNA 2 yes yes c rare >94%
Pfizer mRNA 2 yes yes c rare >94%
Janssen viral vector 1 yes yes yes d <90%
Astra-Zeneca viral vector 2 yes yes c d <90%
yes
a b
Information that was available as of August 2021. In the U.S., an EUA has been given for these vaccines for people aged ≥16, which was
subsequently expanded to ≥12 years of age. c In the U.K., an EUA no longer applies for the Pfizer, Moderna, and Astra-Zeneca vaccines,
which now have been granted final approval for use. In the U.S. as of August 2021, the Pfizer vaccine was given FDA approval, while the
other 3 vaccines are undergoing further evaluation for full approval by the FDA. d Blood clots have been reported in a small number of
mostly female vaccine recipients ≤50 years of age or ≥65 of age for these two vaccines. Myocarditis and pericarditis have occurred rarely
in people ≤30 years of age who received the Moderna or Pfizer vaccine.

As with the general population, people with HIV/AIDS should receive one of the
available vaccines as a preventive measure against developing COVID-19. Interestingly,
in the overall picture, the evidence to date (reviewed in Reference [27]) does not suggest
that HIV/AIDS patients have a markedly higher susceptibility to SARS-CoV-2 infection,
with disparities in the social determinants of health and comorbidities likely having a
greater influence, especially with regards to gaining access to supportive health care
and continuation of ART. There are also other reports from separate facilities describing
increased, decreased, or no difference in outcomes of COVID-19 in this patient population,
especially in terms of the fatality rate [26]. These studies have come from various locations,
each with a different underlying HIV prevalence and access to various ART regimens. The
majority of the published literature has not supported a significantly higher risk for severe
disease among HIV/AIDS patients in the United States and Europe, although a large,
Viruses 2021, 13, 1890 13 of 16

population-based study in South Africa reported a higher rate of death due to COVID-
19 [28]. Higher rates of comorbidities associated with COVID-19 disease severity among
HIV/AIDS patients is an area that still needs to be monitored closely. The immediate
impact of COVID-19 is that it could lead to decreased access to HIV prevention services
and HIV testing, and hampering HIV treatment access and virologic suppression could
lead to worsening of HIV control and other desirable positive outcomes. In addition, along
these lines, the U.S. Centers for Disease Control and Prevention (CDC) has concluded [29]
that people with HIV who are on effective HIV treatment have the same risk for developing
COVID-19 as people who do not have HIV, although the risk for people with HIV getting
very sick is greatest for those who have a low CD4 T-cell count and are not on effective HIV
treatment such as with ART.
Based on the foregoing, a few relevant questions arise as follows: (i) Should HIV/AIDS
patients receive a COVID-19 vaccine? (ii) Are the vaccines safe for this patient population?
(iii) If so, which vaccine should be administered to them? (iv) How often should they
receive booster injections? (v) At what point, if at all, should they be vaccinated after they
have recovered from an infection with SARS-CoV-2? The answers to most of these questions
are relatively straightforward and not complicated. According to the CDC [29], the U.S.
vaccine safety system makes sure all vaccines are as safe as possible. COVID-19 vaccines
have gone through rigorous safety tests and have met or even exceeded similar standards
to those for other vaccines that have been produced for nearly a century and have been in
routine use for over 60 years. People with HIV have been included in clinical trials, though
there is limited safety and efficacy data available as they pertain specifically to this group.
So far, there are no data to suggest that the vaccines are not safe and effective for people
with HIV, including adolescents between 12 and 15 years, nor has it been shown that the
COVID-19 vaccines interfere with the effectiveness of HIV medications such as ART. There
have been no unusual links or enhanced negative reactions between HIV or other types of
immunosuppression with any of the rare serious adverse events that have been reported
for the COVID-19 vaccines. Much of this information has been provided by the British
HIV Association [30] and the World Health Organization [31], who have also indicated
that HIV-infected people generally will likely produce a weaker response to the COVID-19
vaccines, but they are still expected to be protective. This protection, however, may be
to a lesser extent, especially for those individuals with low CD4+ counts (less than 100).
Nonetheless, the U.K. Department of Health recommends that people with HIV, regardless
of their CD4+ count, should receive a COVID-19 vaccine. In addition, because some people
with HIV, especially those with a very low CD4 T-cell count, may be at increased risk
for severe illness due to COVID-19, the CDC recommendation [29] advises that people
with HIV may receive the vaccine as long as they do not have other conditions that would
exclude them, such as a known severe allergic reaction or immediate allergic reaction of any
severity after a previous dose or to a component of the COVID-19 vaccine. The vaccines
authorized for use in the United States and the United Kingdom do not contain infectious
virus so they are expected to be safe in people with low CD4 cell counts. It is worth noting,
however, that while the currently available vaccine products are not live vaccines, in the
traditional sense, the one produced by Jannsen/Johnson & Johnson and Astra-Zeneca uses
a live, but replication-incompetent human adenovirus vector, encoding for the recombinant
SARS-CoV-2 spike (S) glycoprotein, stabilized in its pre-fusion form. The viral vector’s
purpose is to introduce the DNA, which encodes for the spike protein, into the human
body in a somewhat unique way so that multiple copies of it can be produced in vivo, thus
making a repeat (i.e., a booster) injection theoretically less likely to be necessary. Such
a viral vector vaccine is considered to be safe even for immunocompromised patients,
including those with HIV/AIDS, given that the viral vector has been shown to be harmless
in one of the most recently published studies on this topic [32]. Nonetheless, prior to
this finding, there was some initial concern about a potential association observed more
than a decade ago between adenovirus vector-based vaccines and an increased risk of
acquiring HIV infection among men who received this type of vaccine [33]. This unexpected
Viruses 2021, 13, 1890 14 of 16

finding was detected in two HIV vaccine trials that used adenovirus vector-containing
products [34,35], but these vaccines were constructed differently and are not related to
the structure of the COVID-19 vaccines. The reason for this observed HIV risk remains
uncertain, although several follow-up studies have suggested a possible interference in the
HIV-specific vaccine response or in the CD4 cell susceptibility to HIV infection induced
by this kind of vaccine [36,37]. Accordingly, specific studies on this issue with this type
of COVID-19 vaccine should be considered by closely monitoring the response patterns
of HIV-infected people to various immune parameters, which would include periodically
measuring CD4 T-cell counts, viral loads, and anti-spike protein antibody levels subsequent
to being vaccinated. In addition, testing for delayed-type hypersensitivity responses, as
shown recently by Barrios et al. [38] for recovering COVID-19 patients, may also provide
valuable insights on the importance of cellular immune responses mediated by CD8+ T cells
that directly kill virally infected cells as an additional defense mechanism for prospective
vaccinees. There are still, however, other unresolved issues. For example, will the currently
available vaccines be fully protective against variants of SARS-CoV-2, especially the more
recently identified highly invasive/infectious delta variant [39,40], what is the longevity
of protection that is provided by any of these vaccines, and will additional boosters be
needed beyond what is currently being done? Somewhat encouraging news, along these
lines, was recently reported [41] indicating that the Janssen/Johnson & Johnson vaccine
provided lasting protection of at least 8 months duration and it afforded protection against
the delta and other variants. Although there had already been prior preliminary evidence
(reviewed in Reference [42]) supporting an important role for both CD4+ and CD8+ T cells
in the immunologic memory component in the host response to COVID-19, it is likely that
additional related news on these topics will be forthcoming in the coming months. In light
of these potential concerns/issues, it should be realized that, in the final analysis, the overall
benefits of receiving any of the authorized COVID-19 vaccines in a pandemic situation
currently outweigh the potential risks, even for people with impaired immune systems.

Author Contributions: Both authors equally contributed to the conceptualization and writing of the
manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare that they have no conflict of interest. It should be noted
that the citing of commercially available products should not be construed as an endorsement. They
are being cited for the sole purpose of providing examples of vaccines that are in the near-approval
stage, have been approved, or have been given preliminary authorization for use for immunization
purposes by authorizing/governmental agencies, after the manufacturers provided data showing
that they have met the minimal standards for successfully completing and fulfilling the required
clinical trial testing.

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