The Immunocompromised Host: HIV Infection

Abstract

The variety of pulmonary infections encountered in HIV-infected individuals indicates that many components of the host defense network are impaired. In addition to depletion of CD4+ T cell numbers, HIV infection results in functional deficits in CD4+ T cells, CD8+ T cells, and natural killer cells. Although some components of macrophage defense are preserved, lack of activation signals from CD4+ T cells contributes to impaired defense by macrophages. There are few data examining the functional capabilities of neutrophils in the lung, but evidence from peripheral blood neutrophils indicates that defense by these cells is also impaired. An improved understanding of these events in the lung during HIV infection could lead to specific interventions aimed at restoration of deficient function.

Full text

The Immunocompromised Host
HIV Infection
James M. Beck
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School; and Medical Service,
Department of Veterans Affairs Medical Center, Ann Arbor, Michigan
The variety of pulmonary infections encountered in HIV-infected
individuals indicates that many components of the host defense
network are impaired. In addition to depletion of CD4⫹Tcellnum-
bers, HIV infection results in functional de ficits in CD4⫹T cells, CD8⫹
T cells, and natural killer cells. Although some components of macro-
phage defense are preserved, lack of activation signals from CD4⫹
T cells contributes to impaired defense by macrophages. There are
few data examining the functional capabilities of neutrophils in the
lung, but evidence from peripheral blood neutrophils indicates that
defense by these cells is also impaired. An improved understanding
of these events in the lung during HIV infection could lead to specific
interventions aimed at restoration of deficient function.
Keywords: HIV infections; macrophages, alveolar; neutrophils;
opportunistic infections; T-lymphocytes
The variety of pulmonary infections encountered in HIV-
infected individuals demonstrates that HIV impairs lung host
defenses significantly (1). Although most investigations focus
on HIV’s effects on systemic immunity, a significant body of
literature examines pulmonary immune mechanisms during HIV
infection. In some instances, immune defects documented in the
periphery are reflected in the lungs. In other instances, effects
of HIV on lung cells differ from those in the periphery. This
article focuses on the effects of HIV infection on pulmonary host
defenses to explain why serious pulmonary infections remain
common in this immunocompromised patient population.
The accessibility of lung cells for study by bronchoalveolar
lavage (BAL) provides an opportunity to study the effects of
HIV and opportunistic pathogens on lung host defenses. Once
impairments in pulmonary host defense are understood, novel
strategies to correct these defects may be developed for treat-
ment and prophylaxis of pulmonary infections (1).
There are several general mechanisms by which HIV infection
can impair pulmonary host defense; the literature documents
alterations in cell numbers and in cell function. First, HIV di-
rectly infects and kills cells directed against pathogens, leaving
decreased numbers of cells available to participate in host de-
fense. Second, HIV infection induces qualitative defects in the
metabolic and secretory functions of effector cells. Third, HIV-
infected cells may shift their repertoires from elaboration of
immunostimulating to immunosuppressive products. Fourth,
HIV infection could interfere with the capacity of circulating
lymphocytes, monocytes, or neutrophils to migrate into the lungs
and to clear pathogens from the alveolar spaces. Finally, coinfec-
(Received in original form July 30, 2005; accepted in final form August 17, 2005)
Supported in part by a Merit Review Award from the Department of Veterans
Affairs and R01 HL08342 from the National Institutes of Health.
Correspondence and requests for reprints should be addressed to James M. Beck,
M.D., Pulmonary Medicine (111G), Veterans Affairs Medical Center, 2215 Fuller
Road, Ann Arbor, MI 48105. E-mail: jamebeck@umich.edu
Proc Am Thorac Soc Vol 2. pp 423–427, 2005
DOI: 10.1513/pats.200507-077JS
Internet address: www.atsjournals.org
tion by a second pathogen can contribute to a breakdown in the
host defense cascade.
HIV INFECTION OF LUNG CELLS
One important mechanism by which HIV alters lung host de-
fense is by direct infection of pulmonary cells. Various HIV
strains demonstrate tropism for lymphocytes or for monocytes/
macrophages. The CD4 molecule, present on lymphocytes and
monocytes/macrophages, serves as the primary cellular receptor
for HIV-1. In the lung, CD4 is the primary receptor for HIV
on alveolar macrophages. Coreceptors are also needed for HIV
entry into cells, and cellular coreceptors determine the tropism
of HIV strains (Figure 1). Lymphocyte-tropic (T-tropic) strains
interact with the chemokine receptor CXCR4 (fusin) to control
entry into target cells. Infection with T-tropic strains can be
blocked by the CXC chemokine SDF-1, which is a CXCR4
ligand.
In contrast, monocyte-tropic (M-tropic) strains interact with
the chemokine receptor CCR5 to control entry into target cells.
HIV infection of human alveolar macrophages is preferentially
mediated by the CCR5 receptor, although alveolar macrophages
also express CXCR4. Infection with M-tropic strains can be blocked
with the CC chemokines RANTES, macrophage inflammatory
protein-1␣, and macrophage inflammatory protein-1␤,whichare
CCR5 ligands. As HIV infection progresses, T-tropic virus replaces
M-tropic virus, and this change is accompanied by more rapid
immunologic decline.
Alveolar macrophages are a primary reservoir of HIV in
the lung. HIV reverse transcriptase can be detected in alveolar
macrophages obtained by lavage from patients with AIDS, and
alveolar macrophages can be infected with HIV in vitro (2).
Reports comparing the HIV burden of alveolar macrophages
and peripheral blood monocytes are discrepant. The relative
importance of in situ HIV replication in the lung, compared with
the influx of previously infected cells from bone marrow and
blood, is unclear. The percentages of alveolar macrophages ex-
pressing HIV antigens have varied considerably in reports from
different laboratories (3). Detection of HIV by polymerase chain
reaction suggests that HIV infection of alveolar macrophages
is common (4). Alveolar macrophages become infected with
increasing frequency as HIV infection progresses (5). When di-
rect comparisons of alveolar macrophages and peripheral blood
monocytes have been made, the data suggest that viral burdens
in these two cell populations are equivalent (6).
How highly active antiretroviral therapy (HAART) modu-
lates HIV replication in the lung and pulmonary host defense
is unknown. Isolation of HIV from BAL in asymptomatic indi-
viduals decreases when CD4⫹T cell counts are greater than
200/␮l, and when patients receive HAART (7), suggesting a
beneficial effect. However, HIV strains may evolve indepen-
dently in the lung and blood, as phylogenetic analysis of BAL
strains may differ from blood strains in HIV-infected individuals
(8). Zidovudine resistance may differ in peripheral blood mono-
nuclear cells and alveolar macrophages of single individuals,
suggesting that HAART may have different effects on HIV in

424 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 2 2005
Figure 1. Tropism of HIV strains for lung cells. T-tropic strains infect
T cells, using CD4 as the main receptor and CXCR4 as the coreceptor.
M-tropic strains infect alveolar macrophages, using CCR5 as the core-
ceptor, although alveolar macrophages also express CXCR4.
lung cells (9). Recent work comparing resistance patterns of
peripheral blood and BAL cells demonstrates that resistant HIV
genotypes in the lung may be most widely divergent in individu-
als exposed to combination antiretroviral therapy (10). Further
studies are needed to examine the viral load in the lung during
HAART and to determine how HAART modulates pulmonary
host defenses (11).
ALTERATIONS IN LUNG CELL NUMBERS AND
PHENOTYPES DURING HIV INFECTION
Most of the data describing alterations in lung cell numbers and
phenotypes were obtained during bronchoscopies to diagnose
pulmonary infections, making the effects of HIV and of opportu-
nistic pathogens difficult to distinguish. Additionally, these stud-
ies were conducted before the availability of HAART. These
studies revealed that lymphocyte percentages or concentrations
are increased in BAL from HIV-infected individuals compared
with uninfected individuals. Examination of BAL lymphocyte
subsets from patients with AIDS shows decreases in CD4⫹
T cells and increases in CD8⫹T cells. Therefore, CD4/CD8
ratios in BAL specimens may be lower than the ratios in periph-
eral blood. Some HIV-infected individuals may manifest pulmo-
nary symptoms as a result of CD8⫹T-cell influx into the lung,
clinically diagnosed as lymphoid interstitial pneumonitis. Late
in the course of HIV infection, numbers of CD8⫹T cells decline.
Depletion of CD8⫹T cells may be associated with the develop-
ment of disseminated cytomegalovirus and Mycobacterium avium
infections (12). As in peripheral blood, most T cells in the lung
bear ␣␤ T-cell receptors on their surfaces, but a minority of
T cells expresses ␥␦ T-cell receptors. Numbers of ␥␦ T cells are
reported to be decreased or increased in HIV-infected patients
with opportunistic infections.
Macrophage numbers in BAL from patients with AIDS are
probably normal, but percentages are decreased by influx of
other cells. Several BAL series have reported increases in the
concentrations or in the percentages of neutrophils obtained
from patients with AIDS compared with uninfected control sub-
jects. Presumably, HAART results in the repopulation of pulmo-
nary host defense cells as in blood, but BAL studies are not
available to compare individuals receiving and not receiving
HAART.
ALTERATIONS IN LYMPHOCYTE FUNCTION
CD4ⴙT Cells
Recent evidence demonstrates that, in addition to accelerated
destruction of CD4⫹T cells by HIV infection, production of
T cells is also impaired. Underproduction can occur from
infection-mediated death of progenitor cells and destruction of
the hematopoietic stroma. In peripheral blood, T cells from
patients with AIDS do not proliferate normally in response
to mitogens. Even in patients with AIDS who show serologic
evidence of prior infection with cytomegalovirus or herpes sim-
plex virus, T cells fail to proliferate normally in response to these
viral antigens. Failure to proliferate may be caused in part by
impaired elaboration of IL-2. Peripheral blood T cells from pa-
tients with AIDS have impaired IL-2 secretion in response to a
variety of stimuli. In vitro, recombinant IL-2 can restore some
mitogenic responses of blood T cells in patients with AIDS (13).
Clinical trials of IL-2 for HIV infection demonstrate that IL-2
increases CD4⫹T cell counts in recipients without increasing
HIV replication, particularly when given intermittently (14).
IL-16 may prime mature CD4⫹memory cells to respond to
IL-2, and decreased IL-16 levels correlate with HIV progression.
Therefore, IL-16 therapy may be useful in addition to IL-2 to
restore CD4⫹T-cell responses (15).
T cells from HIV-infected individuals do not produce IFN-␥
normally in response to mitogens or antigens. The relative ability
of peripheral lymphocytes to elaborate IFN-␥correlates with
clinical status and CD4⫹T cell count and predicts progression
to AIDS (16). Experimental work suggests that progression from
asymptomatic HIV infection to AIDS is accompanied by a switch
from Th1-like responses to Th2-like responses. In theory, pre-
vention of this switch in T-cell responses could prevent progres-
sion to AIDS. IL-12, a cytokine that favors Th1 development
and inhibits Th2 development, has been shown to restore cell-
mediated immunity in T cells obtained from HIV-infected indi-
viduals (17). Few data exist on the functional capabilities of lung
CD4⫹cells.
CD8ⴙT Cells
As with CD4⫹T cells, CD8⫹T cells in blood and lung can be
infected with HIV. HIV infection also impairs the functional
capacities of CD8⫹T cells. CD8⫹T cells obtained from the
lungs of HIV-infected individuals do not lyse appropriate targets
in vitro (18). For example, CD8⫹T cell–mediated cytotoxicity
for influenza virus is decreased in HIV-infected individuals (19).
Phenotypically, CD8⫹T cells from patients with AIDS show
increased expression of activation markers, compared with unin-
fected individuals, and increased percentages of activated cells
predict progression of HIV-related disease. Peripheral CD8⫹
T cells in HIV-infected individuals may be poor effectors because
they lack required maturation signals (20). An analogous situa-
tion likely exists in the lung.
CD8⫹T-cell alveolitis occurs during HIV infection, but the
functional capabilities of these cells and their intended targets
require further investigation. Subpopulations of CD8⫹T cells,
obtained from HIV-infected individuals, are cytotoxic for macro-
phages or B-cell lines expressing HIV antigens (21). The intensity
of CD8⫹alveolitis correlates with HIV load, and the poor prog-
nosis associated with alveolitis may be a result of the elevated
viral burden (22). Unlike the periphery, local concentrations of
IL-2 and IFN-␥may be increased in the lung during HIV infec-
tion due to activation of CD8⫹T cells (23). The alveolitis may
be driven by overproduction of IL-15, a cytokine with IL-2–like
effects, by alveolar macrophages. Alveolar macrophages from
HIV-infected individuals produce large quantities of IL-15,

Beck: HIV Infection 425
which enhances antigen presentation by alveolar macrophages
and causes proliferation of lung CD8⫹T cells (24).
NK Cells
Increased numbers of NK cells in BAL have been observed in
HIV-infected individuals, but with progressive HIV disease, they
lose functional capabilities. NK cells may be nonfunctional in
HIV infection because they are dependent on signals from
CD4⫹T cells for optimal function (25). Biologic response mod-
ifiers such as recombinant IL-2 restore lytic ability in vitro (26),
and IFN-␥may augment NK cell activity in early stages of HIV
infection (27).
B Cells
Analysis of peripheral B cells from HIV-infected individuals
shows elevated numbers of cells that spontaneously secrete im-
munoglobulins, and patients with AIDS have increases in serum
IgA, IgG, and IgM. The IgG increase is predominantly due to
IgG subtypes IgG1 and IgG3, with decreases in IgG2 and IgG4.
Antibody to polysaccharides in bacterial cell walls is composed
of IgG2, and patients with AIDS who have pyogenic infections
have lower serum IgG2 than patients without bacterial disease.
Concentrations of immunoglobulins in the lung may depend
on the stage of HIV infection or the presence of pulmonary
pathogens. Compared with uninfected individuals, measurement
of immunoglobulins in BAL from patients with AIDS who have
pulmonary symptoms shows increases in total amounts of IgG,
IgM, and IgA. Local immunoglobulin synthesis may occur in the
lung, as shown by increased numbers of IgG-, IgM-, and IgA-
secreting cells (28). However, BAL from asymptomatic HIV-
infected individuals contains decreased concentrations of IgG
compared with uninfected control subjects (29). During HAART,
IgG levels in asymptomatic, HIV-infected individuals are
increased compared with uninfected volunteers (30).
Antibody responses to specific antigens are impaired in HIV-
infected individuals. B-cell abnormalities begin early in HIV
infection, with failure to produce antibody in response to mito-
gen at the time of HIV seroconversion, before T-cell function
is affected. B cells from patients with AIDS show impaired
proliferation in response to mitogens and do not initiate normal
antibody synthesis in response to newly encountered antigens.
Decreased IgG concentrations in the lung may be a result of
impaired ability of alveolar macrophages to induce IgG secretion
from B cells, likely as a result of transforming growth factor-␤
secretion (29).
ALTERATIONS IN MACROPHAGE FUNCTION
Phagocytosis, Respiratory Burst, and Killing of Organisms
Peripheral blood monocytes from patients with AIDS are re-
ported by some investigators to be defective in chemotaxis to
several chemoattractants, but other investigators find unim-
paired chemotaxis. Alveolar macrophages from asymptomatic,
HIV-infected subjects demonstrate enhanced phagocytosis for
Staphylococcus aureus (31). BAL cells from HIV-infected individu-
als demonstrate increased fungistatic activity against Cryptococcus
neoformans compared with cells from uninfected control subjects
(32). The magnitude of the respiratory burst of alveolar macro-
phages from patients with AIDS in vitro is not different from
uninfected control subjects, and IFN-␥enhances the response in
cells from both groups equivalently (33). Alveolar macrophages
and monocyte-derived macrophages do not kill Toxoplasma gondii
or Chlamydia psittaci, whether obtained from patients with AIDS
or from uninfected individuals (33). When exposed in vitro to
IFN-␥, alveolar macrophages obtained from patients with AIDS
increase their killing of these organisms in a manner equivalent
to uninfected individuals’ cells (33). In contrast, HIV infection
may impair phagocytosis of organisms that commonly cause
pulmonary infections in susceptible individuals. For example,
alveolar macrophages from HIV-infected individuals demon-
strate decreased binding and phagocytosis of Pneumocystis
in vitro, and this defect correlates with decreased expression of
alveolar macrophage mannose receptors (34).
Antigen Presentation
During HIV infection, blood monocytes do not present antigens
to T cells normally (35). In comparison to blood monocytes,
alveolar macrophagesare considered to be relatively poor antigen-
presenting cells. However, alveolar macrophages from HIV-
infected patients have enhanced ability to present antigen com-
pared with alveolar macrophages from uninfected control subjects
(36). Dendritic cells are also important antigen-presenting cells
in the lung. HIV infection of dendritic cells is cytopathic for
these cells, and the numbers of dendritic cells are decreased
in asymptomatic HIV-infected individuals and in patients with
AIDS (37). Dendritic cells from HIV-infected individuals exhibit
defective antigen presentation and may facilitate HIV infection
of T cells (38).
Tumor Necrosis Factor Elaboration
Some patients with AIDS are reported to have elevated serum
levels of tumor necrosis factor (TNF). When peripheral blood
monocytes are examined, they are reported to have high sponta-
neous release of TNF (39) or suboptimal release after appro-
priate stimulation (40). Other investigators have found that HIV
infection of monocytes or monocyte-derived macrophages in vitro
does not induce TNF release (41). Alveolar macrophages from
asymptomatic, HIV-seropositive individuals have increased spon-
taneous TNF release, which correlates with extent of HIV expres-
sion (42). BAL cells from smokers release less TNF than BAL
cells from nonsmokers, suggesting that smoking and HIV inter-
act to suppress macrophage function (43). In the lung, TNF
decreases HIV replication in alveolar macrophages by inducing
production of RANTES and by decreasing CCR5 expression (44).
ALTERATIONS IN NEUTROPHIL FUNCTION
Although patients with AIDS may have increased numbers of
neutrophils at the time of BAL, little is known about the host
defense capabilities of these cells. In several studies, peripheral
neutrophils from some patients with AIDS who had frequent
localized infections showed decreased chemotaxisin vitro.Neutro-
phils from HIV-infected individuals have decreased expression of
CD88, the ligand for C5a, which could contribute to increased
susceptibility to bacterial infections (45). Recently, pulmonary
neutrophils from HIV-infected individuals have been shown to
express decreased immunoglobulin G Fc-␥receptor 1 expression
compared with neutrophils from uninfected volunteers (46).
The phagocytic capacity of neutrophils during HIV infection
is controversial and may depend on the stage and severity of
HIV infection. For example, neutrophils from individuals with
early HIV infection demonstrate enhanced phagocytosis (47).
Phagocytosis of opsonized S. aureus is decreased in the periph-
eral blood neutrophils of some, but not all, patients with AIDS
(48). The defect in phagocytosis can be corrected by in vivo
administration of granulocyte colony-stimulating factor (49).
Other investigators find decreased phagocytosis and intracellular
killing of Candida albicans by neutrophils obtained from intrave-
nous drug-using patients with AIDS, whereas cells from homo-
sexual AIDS patients function normally (50). The authors postu-
late that these defects are associated with intravenous drug use

426 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 2 2005
rather than HIV infection because cells from seronegative intra-
venous drug users were also abnormal.
The neutrophil possesses potent oxygen-dependent mecha-
nisms to kill intracellular organisms. Peripheral neutrophils from
patients with AIDS are reported to produce subnormal, normal, or
supernormal amounts of superoxidewhen stimulated with phorbol
myristate acetate. The ability of pulmonary neutrophils from HIV-
infected individuals to produce superoxide is unknown.
CONCLUSION
HIV infection impairs many aspects of host defense in the lung
and in the periphery. In addition to depletion of CD4⫹T cell
numbers, HIV results in functional deficits in CD4⫹T cells,
CD8⫹T cells, and NK cells. Although some components of
macrophage defense are preserved, lack of activation signals
from CD4⫹T cells contributes to impaired defense by macro-
phages. There are few data examining the functional capabilities
of neutrophils in the lung, but evidence from peripheral blood
neutrophils indicates that defense by these cells is also impaired.
An improved understanding of these events in the lung during
HIV infection can lead to specific interventions aimed at restora-
tion of deficient function.
Conflict of Interest Statement :J.M.B. does not have a financial relationship with
a commercial entity that has an interest in the subject of this manuscript.
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