HIV-1 and HIV-2 infections in Guinea-Bissau, West Africa : studies of immune responses, prevailing viruses and epidemiological trends

Abstract: This thesis encompasses immunological, virological and epidemiological studies of HIV-1 and HIV-2 infections in Guinea-Bissau. We have established a robust and reliable diagnostic strategy based on a combination of enzyme-linked immunosorbent assays (ELISAs) and rapid simple tests. Evaluations showed that the strategy had a high capacity to discriminate between HIV-1 and HIV-2 and a high concordance with polymerase chain reaction (PCR) testing. Epidemiological studies including annual sentinel surveillance of pregnant women and a prospective cohort study of police officers revealed gradually increasing prevalence rates but relatively stable incidence rates for HIV-1, and significantly decreasing prevalence and incidence rates for HIV-2 over a seven- to ten-year period. A study of a possible protective effect of HIV-2 infection against subsequent HIV-1 infection could not confirm a previous report by others of such an effect. The prevailing virus variants were characterized and it was demonstrated that a majority of the HIV-1 variants circulating in Guinea-Bissau and neighbouring countries are subtype A/G recombinants. Comparative viral load measurements revealed that the plasma viral load was significantly lower in HIV-2-infected as compared to HIV-1-infected individuals and that the viral setpoint after primary infection was 28-fold lower for HIV-2 as compared to HIV-1. The plasma viral load was inversely correlated to CD4+T-lymphocyte levels for both HIV-1 and HIV-2. HIV-1 and HIV-2 dually infected individuals carried virus of the same genetic subtypes as the singly infected persons but the viral load measurements were less predictable without apparent correlation with CD4+ T-lymphocyte levels. Assays for HIV-2-specific cell-mediated immune responses and mitogen-induced ßchemokine production established in conjunction with HIV-2 monkey vaccine studies at the Swedish Institute for Infectious Disease Control (SMI) were subsequently applied for human investigations in Guinea-Bissau. In monkeys, lymphocyte proliferative responses and CTL were readily detectable after HIV-2 infection and in a proportion of animals immunized with an HIV-2 recombinant canarypox virus vaccine alone or in combination with HIV-2 gp125 or V3 peptide boosters. Four out of ten primeboost immunized monkeys but none of four monkeys given the HIV-2 recombinant vaccine alone were protected against intravenous challenge with live HIV-2. However, no clear correlation between the cell-mediated immune responses and protection against live HIV-2 challenge was observed. Studies of HIV-2 discordant couples in Guinea-Bissau showed that HIV-2 infected as well as HIV-2 exposed uninfected individuals had increased HIV-2 specific T-lymphocyte proliferative responses compared to control subjects. The exposed uninfected individuals had reactivity to HIV-2 V3 peptides while the HIV-2-infected persons mainly reacted to HIV-2 whole viral lysate. Quantification of mitogen-induced CD8+ T-cell production of ß-chemokines (RANTES, MIP-1[alpha], MIP-1ß, which are known to suppress HIV replication, showed increased production in HIV-2-infected and HIV-2-exposed uninfected individuals as well as in HIV-seronegative outpatients as compared to seronegative healthy controls. The demonstrated immune responses associated with HIV-2 infection and exposure to HIV-2 could be important for resistance to this infection and control of disease progression. These investigations have given some new insight into the characteristics of HIV-1 and HIV-2 infections and provide a basis for continued studies of these infections in Guinea-Bissau.