Differences in HIV-Specific T Cell Responses between HIV-Exposed and -Unexposed HIV-Seronegative Individuals

Abstract

HIV-1-specific T lymphocyte responses in individuals exposed to HIV-1 but who remain persistently seronegative (HESNs) have been reported in some but not all previous studies. This study was designed to resolve unequivocally the question of whether HESNs make HIV-1-specific T cell responses. We performed a blind investigation to measure HIV-1-specific T cell responses in both HIV-1-serodiscordant couples and HIV-1-unexposed seronegative controls (HUSNs). We found low-frequency HIV-1-specific T cells in both HESNs and HUSNs but show that the response rates were higher over time in the former (P ‫؍‬ 0.01). Furthermore, the magnitudes of the HIV-1-specific T cell responses were significantly higher among responding HESNs than among HUSNs over time (P ‫؍‬ 0.002). In both groups, responses were mediated by CD4 T cells. The responses were mapped to single peptides, which often corresponded to epitopes restricted by multiple HLA-DR types that have previously been detected in HIV-1-infected patients. HIV-1-specific T cell responses in HUSNs and some HESNs likely represent cross-reactivity to self or foreign non-HIV-1 antigens. The significantly greater T cell responses in HESNs, including in two who were homozygous for CCR5⌬32, demonstrates that HIV-1-specific T cell responses can be induced or augmented by exposure to HIV-1 without infection.

Quantitative and Qualitative Differences in the T Cell Response to HIV in Uninfected Ugandans Exposed or Unexposed to HIV-Infected Partners

“…The response rates and frequencies of T cells specific for influenza virus, cytomegalovirus, and Epstein-Barr virus were higher than those specific for HIV and not significantly different between HESN and HUSN, suggesting that HUSN were not particularly sheltered from environmental exposure to common viruses, nor did they have had intrinsic T cell responsiveness defects. Within the limits of the cultured ELISPOT assay, the response rate to HIV subtypes A and D in HUSN parallels findings in studies with B subtype in the United Kingdom and C subtype in Malawi (21). In that study and in the present one, strict criteria for the definition of the HESN and HUSN groups and for the quality control of ELISPOT responses were used; thus, the baseline responses observed in HUSN are likely to represent cross-reactivity with other undefined environmental exposures.…”

“…In the present study, we wanted to answer the question of whether the induction of T cell-mediated immune responses to HIV occur in exposed uninfected individuals with a well-defined heterosexual exposure to HIV compared to a companion study (21) involving predominantly homosexual exposure. To this end, we enrolled Ugandan HIV serodiscordant couples who declared Ն25 episodes of unprotected heterosexual sexual intercourse in the previous year.…”

HIV-1-Specific Enzyme-Linked Immunosorbent Spot Assay Responses in HIV-1-Exposed Uninfected Partners in Discordant Relationships Compared to Those in Low-Risk Controls

“…The study was limited by the fact that we performed only one type of immune assay on unfractionated PBMC, making it difficult to distinguish CD8 ϩ and CD4 ϩ responses. CD4 responses to peptides restricted to multiple HLA-DR types have recently been shown to contribute to ELISpot responses observed in HESN and low-risk controls (42). We had limited ability to confirm responses using frozen samples due to limited numbers of PBMC.…”

HIV-Specific CD4 T Cell Responses to Different Viral Proteins Have Discordant Associations with Viral Load and Clinical Outcome

“…In particular, studies have demonstrated that the presence of HIV-specific CD4 T cells is enriched in individuals spontaneously able to control viral replication in the absence of antiretroviral therapy (8,16,21). Furthermore, the presence of HIV-specific CD4 T cells in highly exposed but HIV-seronegative individuals also suggests a protective role for this cellular subset (20). In addition, it is important to note that although a small percentage of HIV-specific CD4 T cells are preferentially targeted by HIV, the vast majority of these cells remain uninfected at all times in vivo (6), where they are likely to mediate an important antiviral role.…”