The role of HIV gp120 in the disruption of the immune system.
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.
- SourceAvailable from: Wim Jennes[Show abstract] [Hide abstract]
ABSTRACT: Twenty years after its discovery, HIV has become the world’s number one killer among infectious diseases. An HIV vaccine may prove the best hope for controlling the HIV pandemic, especially in developing countries where antiretroviral therapy is unlikely to become fully available in the near future. An effective, broad-spectrum HIV vaccine is needed that generates long-term immune memory and protection at the site of infection, particularly at the mucosal sites where the virus gains entry into the body. Understanding of the immunological mechanisms that protect against infection with HIV is of great importance for the design of such a vaccine. However, despite numerous research efforts, a clear correlate of protective immunity against HIV infection has yet to be identified. 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). Decreased in vivo expression of the HIV-coreceptor CXCR4 on the major HIV target cells, CD4+ T cells, was noted. Although CXCR4 downregulation was associated with a prolonged duration of sex work, it may likely not be HIV-protective since HIV-1 strains that are sexually transmitted use CCR5 and not CXCR4 as a coreceptor for cell entry. No differences were found in CCR5 expression, and in frequencies of T cells expressing the HIV-protective beta-chemokines or Th1 and Th2 cytokines. ESN FSWs showed a downregulated rejection response against foreign cells, since in vitro allostimulation resulted in decreased lymphocyte activation and decreased secretion of beta-chemokines and Th1 cytokines. Tolerance against alloantigens may prevent CD4-bearing cells from becoming susceptible HIV targets by mucosal allogeneic activation. 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. HIV-specific CD4+ and CD8+ T cell responses among ESN FSWs were generally of low level and difficult to detect with standard methods like the enzyme linked immunosorbent spot (ELISPOT) assay. In order to increase the sensitivity of detection of antigen-specific T cells, the Amplispot assay was developed as a modification of the ELISPOT assay by the addition of the recombinant cytokines IL-7 and IL-15. In comparison with the ELISPOT assay, the Amplispot assay showed up to 7-fold increased sensitivity for freshly isolated white blood cells, and up to 18-fold for cryopreserved white blood cells. This method may prove particularly useful for the detection of low-level HIV-specific T cell responses in cryopreserved samples, in ESN subjects, and in subjects participating in future trials testing the immunogenicity and efficacy of experimental HIV vaccines. 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.PhD thesis, University of Antwerp. 12/2003;
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ABSTRACT: The mechanisms by which HIV-1 induces chronic pathogenic immune activation associated with disease progression remain unclear despite many years of AIDS research. One proposal suggests that sequence and structural mimicry between gp120 and HLA may endow HIV with the capacity to arouse alloreactive and autoimmune responses within the susceptible host, fueling disease progression in a manner similar to graft-versus-host disease (GVHD). Both gp120 and HLA share a common functional interaction with CD4 but also demonstrate peptide binding properties. Here we report the conserved nature of this feature across HIV-1 envelopes, the crucial role of the HLA homologous C5 region for peptide interactions, and the elimination of this property through specific antibody targeting. Given that the C5 domain mimics a HLA activation domain and the reported clinical benefits associated with nonneutralizing antibodies against this region, targeting the C5 domain may have use as a therapeutic vaccine to protect against disease progression.AIDS research and human retroviruses 07/2008; 24(6):845-55. · 2.18 Impact Factor
- Advances in Cancer Research - ADVAN CANCER RES. 01/2008; 101:349-395.