Article

The role of HIV gp120 in the disruption of the immune system.

Department of Oncology, St. George's Hospital Medical School, London, UK.
Immunology Letters (Impact Factor: 2.34). 04/1999; 66(1-3):81-7. DOI: 10.1016/S0165-2478(98)00163-1
Source: PubMed

ABSTRACT The existence of HIV positive individuals who do not appear to progress to disease, or do so only very slowly (LTNPs), strongly suggest that factors other than virus pathogenicity determine disease. The occurence of HIV infected chimpanzees that remain disease free and other African SIV infected primates where disease is apparently species specific underscores the importance of host factors [1,2]. We have examined the immune response of LTNP patients using a variety of techniques including intracellular cytokine FACscan, anchor PCR analysis of the T cell receptor and HLA typing of class II genes by DNA sequencing. Our results to date confirm that the development of disease is consistent with activation of a susceptible immune system, and that this could be due to the fact that HLA-like sequences of HIV may 'allo' activate the host immune response. In order to test this hypothesis further we have examined whether gp120 itself can bind and present specific peptides which may be capable of eliciting 'allo' activation responses in particular hosts.

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Subjects who are frequently exposed to HIV without becoming infected (HIV-exposed seronegative or ESN) are being identified in several at-risk populations, including regular partners of HIV-infected subjects, female sex workers (FSWs) in high-prevalence areas, intravenous drug users exposed to HIV by needle-sharing, and hemophiliacs that have repeatedly been infused with HIV-contaminated blood products. These subjects constitute ideal populations to study potential mechanisms of protection against HIV. In this thesis, in an effort to identify the correlates of protective immunity, innate and adaptive immune responses with potential anti-HIV activity were studied in ESN FSWs at high risk for HIV infection in comparison with HIV-seronegative low-risk female blood donors in Abidjan, Côte d’Ivoire. ESN FSWs showed increased in vivo activation of CD8+ T cells, which could be a sign of ongoing anti-HIV activity by CD8+ cytotoxic T lymphocytes (CTL). 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While beta-chemokines did not show a protective effect among ESN FSWs, their potential role in protection against HIV disease progression was studied further in HIV-infected FSWs in Abidjan, Côte d’Ivoire. Increased intracellular beta-chemokine levels in HIV-infected FSWs were rather a sign of HIV disease progression since they correlated directly with T cell activation and HIV-1 viral load, and inversely with CD4+ T cell counts. Intracellular and secreted beta-chemokine levels were found to correlate positively among HIV-negative controls but not among HIV patients. Secreted beta-chemokine levels per unit of beta-chemokine-positive lymphocyte were decreased in HIV patients for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta and increased for RANTES (regulated upon activation, normal T cell expressed and secreted), suggesting a disrupted beta-chemokine secretory capacity, in addition to increased intracellular beta-chemokine levels, as a sign of HIV disease progression. These data explain the contradictory conclusions concerning the role of beta-chemokines in HIV infection, depending on the applied methodology of detection. HIV-specific CD4+ helper T cells and CD8+ CTL responding to HIV-1 Env- and Gag proteins and to HIV-1 Gag peptide pools were detectable in a subset of ESN FSWs. CD4+ and CD8+ T cell responses among ESN FSWs showed a lower magnitude than among HIV-infected FSWs, but were potentially targeted against different regions of HIV-1 Gag. Future identification of the single peptide responses among ESN FSWs may reveal specific HIV epitopes to which protective T cell immunity is primed, and which should be included in candidate HIV vaccines. Remarkably, detection of HIV-specific T cell responses correlated with the frequency rather than with the duration of HIV exposure among ESN FSWs, suggesting the need for persistent antigenic exposure for the induction and maintenance of HIV-specific T cells among ESN FSWs. 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At present, the meaning of the observed immunological correlates among ESN FSWs can only be hypothesised, as definite proof of HIV-protective capacity will require longitudinal studies that follow-up on the seroconversion status of ESN FSWs. Although it cannot be excluded that these immune factors constitute epiphenomena of sexual exposure by itself, the data provided in this thesis may indicate that protection against HIV infection among ESN FSWs is multifactorial in nature, consisting of HIV-neutralising IgA antibodies, HIV-specific T helper cells and CTL, and possibly suppressed alloimmune responses. Inducing these protective conditions by currently used vaccination strategies may likely prove to be difficult, and specific solutions should be found to address the need for maintenance of humoral and cellular immune responses at the site of viral challenge by persisting antigen.
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