Andrew James Mcmichael

Distinct recognition of closely-related HIV-1 and HIV-2 cytotoxic T-cell epitopes presented by HLA-B*2703 and B*2705.

HIV-1 infection is increasing in many countries where HIV-2 is endemic so the potential interaction between the two strains which differ at the nucleotide level by 40--60% is important. HIV-2 infection is less aggressive than HIV-1 and may protect against HIV-1 infection but this theory is controversial. HIV-specific cytotoxic T lymphocytes (CTL) recognizing conserved viral proteins could mediate cross-immunity. We described extensive cross-reactivity between HIV-1 and HIV-2 CTL epitopes from gag pol and nef presented by HLA-B35. Cross-reactivity was also reported for an HLA-B*2705-restricted HIV-1 epitope; however most CTL epitopes are not cross-reactive (e.g. those presented by HLA-B8 in p17 by HLA-B8 and B14 in gp41 by HLA-CW4 in gp120 and by HLA-B53 in HIV-2 gag). Amino-acid substitutions between HIV-1 and HIV-2 can prevent binding to the HLA molecule or interfere with T-cell receptor (TCR) recognition and may also interfere with recognition of the index sequence. This process of TCR antagonism has been described for naturally occurring variants of HIV-1 hepatitis B virus Epstein--Barr virus and Plasmodium falciparum. (excerpt)

P20-19 LB. Extensive HLA-driven viral diversity following a single-source HIV-1 outbreak in rural China

Background: High rates of mutation in HIV infected individual allow the virus to adapt rapidly in vivo to selective forces such as anti-retroviral therapy (ART) and host immune pressure. This provides an opportunity to determine the relative contribution of different components of the immune response to HIV-1 infection in driving viral diversity, which may also facilitate assessment of their role in controlling viral replication. It is accepted that HIV-1-specific cytotoxic T-lymphocytes (CTL) may drive the selection of viral variants that can escape T-cell recognition but the extent of this selective pressure has been controversial. Methods: Two digit HLA typing; ELISPOT assay; HIV-1 sequence analysis; HIV sequence clustering and phylogenetic analysis of HLA associations using the neighbour-joining method, S-Plus 8.0, “Partitioning around medoids” (PAM) method and Stratification analysis by Mantel-Haenszel tests Results: Here we describe the consequences of HLA-associated selection on viral diversity in the main targets of T-cell recognition following an outbreak of HIV-1 in a cohort of 258 former plasma donors in rural China. The surprising finding that all the donors appear to have been infected with the same strain of clade B HIV-1 ensured that the analysis was not confounded by “founder effect”. At least 32.63% (232/711) of the mutations in the gag, pol and nef genes leading to amino acid substitutions were associated with class I HLA molecules: of these, 27.16% (63/232) were found within or close to known CD8+ T-cell epitopes. Conclusion: Taken together our data confirm that CD8+ T-cell pressure has a major impact on HIV-1 viral diversity and represent an important element of viral control in the infected host.

Lung Immunology and HIV

Infection with the human immunodeficiency virus (HIV) results in a wide spectrum of clinical illness from the rapidly fatal to the chronically indolent. Cohort studies of HIV type-1 (HIV-1) infected individuals in the USA and Europe place the median time for HIV-1 infection to the development of the acquired immunodeficiency syndrome (AIDS) at approximately 8 to 10 years (Schrager et al., 1994). AIDS can occur in as little as 2–4 months (Isaksson et al., 1988) while some infected individuals have remained healthy for more than 12 years (Lifson et al., 1991). The outcome of the progressive deterioration of the immune system that occurs in the majority of patients infected with HIV is clinically apparent disease, manifest with either severe and persistent constitutional signs and symptoms or an opportunistic infection or neoplasm.