When it comes to susceptibility to HIV infection, not all
CD4 T cells are created equal. There are a variety of factors that have been shown
to influence how readily HIV gains entry and replicates, with the
best-described distinction being between activated CD4 T cells, which are
highly susceptible, and resting CD4 T cells, which are relatively resistant. The
particular types of cytokines and chemokines that a CD4 T cell makes have also
been shown to influence the efficiency of HIV infection. Less well understood
is the influence of antigen specificity—the pathogen being targeted by the CD4
T cell. Evidence has been published showing that TB-specific CD4 T cells are highly susceptible, whereas those responding to the
viral infection CMV are relatively resistant (with this resistance being
associated with the release of beta-chemokines capable of binding the CCR5
receptor and blocking HIV entry). A study by Haitao Hu and colleagues from the
U.S. Military HIV Research Program has now explored this issue further by looking
at the susceptibility of various pathogen-specific CD4 T cells and the relationship with the genes that the different cells express.
The results confirm that CMV-specific CD4 T cells are highly
resistant to HIV, but not just due to the release of beta-chemokines: gene
expression analyses revealed that the cells also upregulate several innate
antiviral factors such as IFIT1 (a protein that recognizes a particular form of
viral RNA). Because of these factors, CMV-specific CD4 T cells displayed
reduced susceptibility to HIV infection even when the researchers used antibodies to
neutralize any effect of beta-chemokines. In contrast, CD4 T cells specific for tetanus toxoid (TT) and Candida exhibited a pro-inflammatory Th17-type profile
and were highly permissive to HIV infection. The
researchers suggest that these differences in susceptibility may contribute to
the well-documented relationship between differing levels of immune deficiency and risk of
specific opportunistic infections; i.e., candidiasis is typically an early sign
of immune deficiency whereas active CMV disease occurs almost exclusively at
extremely low CD4 T-cell levels.
Another important implication of the study is that HIV vaccines should aim to induce HIV-specific CD4 T cells with a
profile that resembles CMV-specific responses. The researchers speculate that
there may be a connection between their observations and the fact that the best
results obtained to date in the stringent SIV/macaque model of vaccination have involved a CMV-based vaccine vector. Several research groups—including those of
Louis Picker at the Oregon Health & Science University and Rafick-Pierre Sékaly at the Vaccine & Gene Therapy Institute of Florida—are now working
to develop CMV-based HIV vaccine vectors with the aim of conducting human
studies in both the therapeutic and preventive contexts.
Blood. Published online before print, December 20, 2012. doi:
10.1182/blood-2012-07-446278
Haitao Hu1, Martin Nau1, Phil Ehrenberg1, Agnes-Laurence
Chenine1, Camila Macedo1, Yu Zhou2, Z. John Daye3, Zhi Wei4, Maryanne Vahey1,
Nelson L Michael1, Jerome H Kim1, Mary Marovich1, and Silvia Ratto-Kim1
1 US Military HIV Research Program, Walter Reed Army
Institute of Research, Silver Spring, MD, United States;
2 Department of Pathology and Laboratory Medicine, Temple
University, Philadelphia, PA, United States;
3 Division of Epidemiology and Biostatistics, University of
Arizona Mel and Enid Zuckerman College of Public Health, Tucson, AZ, United
States;
4 Department of Computer Science, New Jersey Institute of
Technology, Newark, NJ, United States
ABSTRACT
In HIV infection, the CD4 responses to opportunistic
pathogens like Candida albicans are lost early, but cytomegalovirus
(CMV)-specific CD4 response persists. Little is currently known about HIV
infection of CD4 T cells of different pathogen/antigen specificity. CFSE-labeled
PBMC were stimulated with CMV, Tetanus Toxoid (TT) and Candida antigens and
subsequently exposed to HIV. HIV infection was monitored by intracellular p24
in CFSE-low population. We showed that while TT- and Candida-specific CD4 T
cells were permissive, CMV-specific CD4 T cells were highly resistant to both
R5 and X4 HIV. Quantification of HIV DNA in CFSE-low cells showed a reduction
of strong-stop and full-length DNA in CMV-specific cells compared to TT- and
Candida-specific cells. β-chemokine neutralization enhanced HIV entry and
infection in TT- and Candida-specific cells, whereas HIV infection in
CMV-specific cells remained low despite increased HIV entry by β-chemokine
neutralization, suggesting post-entry restriction of HIV replication by
CMV-specific cells. Microarray analysis (GEO Accession Number: GSE42853)
revealed distinct transcriptional profiles that involved selective upregulation
of comprehensive innate antiviral genes in CMV-specific cells, whereas TT- and
Candida-specific cells mainly upregulated Th17 inflammatory response. Our data
suggest a mechanism for persistence of CMV-specific CD4 response and earlier
loss of mucosal Th17-associated TT- and Candida-specific CD4 response in AIDS.
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