Human Immunodeficiency Virus-Specific Responses in Adult Ugandans: Patterns of Cross-Clade Recognition

Abstract

Human immunodeficiency virus (HIV) or AIDS is currently the leading cause of death in Uganda, with at least three HIV clades (subtypes) accounting for most new infections. Whether an effective vaccine formulated on viruses from a single clade will be able to protect against infection from other local clades remains unresolved. We examined the T-cell immune responses from a cohort of HIV-seropositive individuals in Uganda with predominantly clade A and D infections. Surprisingly, we observed similar frequencies of cross-clade T-cell responses to the gag, env, and nef regions. Our data suggest that the level of viral sequence variability between distinct HIV strains does not predict the degree of cross-clade responses. High sequence homologies were also observed between consensus peptides and sequences from viral isolates, supporting the use of consensus amino acid sequences to identify immunogenic regions in studies of large populations.Human immunodeficiency virus (HIV) or AIDS continues to be the leading cause of death in sub-Saharan Africa. Although there is a critical need for an effective HIV vaccine, the undefined correlates of protective immunity in HIV type 1 (HIV-1) infection remain an important obstacle. Nevertheless, a wealth of evidence suggests that a robust cellular immune response may curtail viral replication; therefore, HIV vaccine designs have, to date, focused on eliciting strong cellular immune responses.T-cell epitope recognition is dependent on the individual class I human leukocyte antigen (HLA) alleles. The pattern of antigen recognition and immunodominance may be driven by the prevalence of these alleles in the studied population (19). The identification of highly immunogenic and conserved regions is also complicated by HIV sequence diversity (8). T-cell responses against HIV can, in turn, influence the HIV populations in generating immune escape viral variants (33).There is comprehensive data on T-cell epitopes for HIVinfected individuals of Caucasian descent. However, there is a relative paucity of information for the geographic regions where the HIV epidemic is spreading the fastest at this time, particularly sub-Saharan Africa (1,2,7,34,35). In Uganda, clades A and D (as well as A/D recombinant strains) are responsible for approximately 95% of HIV-1 infections (3,11,22,23). Previous studies of HIV-1-specific cellular immune responses in small cohorts of HIV-infected individuals and vaccine recipients in Uganda have shown cross-clade immune recognition (5, 6, 31). Nevertheless, the issue of whether an effective vaccine formulated on viruses from a single clade could protect equally well against viruses from other local clades remains unresolved.We evaluated the pattern of T-cell antigen recognition in the context of the HLA alleles and multiple circulating HIV subtypes in a cross-sectional study of HIV-infected Ugandan adults. We investigated factors that determine cross-clade Tcell recognition in the context of vaccine design for Uganda and sub-Saharan Africa. MATERIALS AND METHODS St...

Clade-Specific Evolution Mediated by HLA-B*57/5801 in Human Immunodeficiency Virus Type 1 Clade A1 p24

“…While CD8 ϩ T-cell cross-clade recognition has been tested extensively (6,11,19,36,48), few studies have addressed the possibility of clade-specific escape from CD8 ϩ T-cell responses. This may be especially relevant where clade consensus sequences differ in immunologically relevant epitopes.…”

HIV-Specific IL-10-Positive CD8+ T Cells Are Increased in Advanced Disease and Are Associated with Decreased HIV-Specific Cytolysis

“…Institutional Review Board approvals were obtained from the California Department of Health Services and the JCRC, and all study participants gave written informed consent. Absolute numbers of CD4 ϩ T cells were determined by BD TruCount (BD Biosciences) and the HIV-1 RNA level was determined from plasma using the Roche Amplicor 1.5 (Roche), as per manufacturer's recommendations, and the lower limit of detection was 400 copies/ml (26). Isolation of PBMC was performed by Ficoll-Hypaque (Amersham Biosciences) density centrifugation.…”

HIV viral diversity and escape from cellular immunity

“…However, because the analyses were based on responses to peptide pools, the data do not rule out the possibility that "cross-clade" responses were directed mainly against epitopes conserved between clades, rather than reflecting true cross-reactivity. Similarly, the analysis of cross-clade responses between Ugandan clades A and D and Chinese B' and C/B' viruses as well as IIIB also did not exclude this possibility [49,50]. Thus, detailed single-peptide-based analyses are needed to accurately assess the potential for cross-clade reactivity.…”