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
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.