HIV-2 genetic evolution and viral dynamics

HIV-2 is less pathogenic and less transmissible compared to HIV-1. This is believed to be due to the lower viral load that is seen in HIV-2 infected patients. However, why this lower viral load is seen is not known. In this thesis we have investigated different aspects of HIV-2 in order to understand the pathogenesis of HIV-2 better. In paper I genetic variation and evolution in the pol gene was studied, with special interests in resistance-associated mutations in HIV-2 infected patients failing antiretroviral treatment. We observed some mutations known to cause resistance in HIV-1 such as M184V, Q151M and E219D; but most resistance mutations appeared to differ from what is known in HIV-1. The main conclusion from this work is that specific algorithms for HIV-2 resistance interpretation are needed, because the algorithms for HIV-1 cannot be used. In paper II we studied the evolution of co-receptor usage, neutralization escape and env gene sequence. We report a switch from CCR5 to CXCR4 using virus during disease progression. We did not see a clear pattern of neutralization escape as is seen in HIV-1. We saw a pattern of changes in the number of potential N-linked glycosylation sites during disease progression. HIV-2 has fewer potential N-linked glycosylation sites in V3. We propose that HIV-2 V3 is more open and accessible to neutralizing antibodies. In paper III and IV we have studied the rate of viral clearance in HIV-2 infected patients as well as in experimentally SIV infected macaques. In paper III we conclude that the clearance of actively virus producing cells appears to be similar in HIV-1 and HIV-2 infection. Thus, we estimated a t½ for virus producing cells of 2.2 and 2.0 days respectively in two HIV-2 patients who started antiretroviral therapy. These findings indicate that differences in pathogenesis between HIV-1 and HIV-2 are not due to differences in viral clearance or life span of virus producing cells. In paper IV we studied the decay of plasma virus in SIV-infected macaques that received aggressive antiretroviral therapy. In these animals we observed a very fast half-life of virus producing cells, 0.5 days, which is the shortest ever reported for any lentivirus. This might be due to the high potency of the antiretroviral therapy or differences between in SIV-infected monkeys and HIV-infected humans