Effect of HIV-1 viral characteristics on mother-child transmission of HIV-1.

摘要

It has now been a sobering 24 years since the hallmark cases of the AIDS pandemic began to be noticed. Since that time a great deal of energy has gone into halting the progression and spread of this plague. But we are still not there, and despite our best efforts at prevention and treatment, the outbreak goes on unabated. In the developed world the available prevention and treatment has almost eliminated the threat of mother to child transmission of HIV-1. However, in the developing world, this type of transmission is still a cruel reality. Mother-child HIV-1 transmission can be prevented in two ways, through prevention of maternal infection with a vaccine, or through prevention of a child's infection with drugs and avoidance of breast-feeding. Studying and understanding viral genetic factors which influence transmission, and give the virus its virulence will be important for the design of new drugs which may be used in treatment and prevention, and may provide targets for a vaccine.; We began our study of viral genetic factors by looking at the influence of viral subtype on mother-child transmission of HIV-1. Our examination of the subtype of the HIV-1 protease gene led us to the conclusion that in Kenya, there is no difference between HIV-1 subtype and rates of transmission from a mother to her child. But, as oft happens in science, one study led us to another question. Our inability to amplify the protease genes of a number of women in our study group led us to the observation that these women seldom transmit HIV-1 to their children. Use of epidemiological methods helped us establish that women for whom the protease gene was non-amplifiable were significantly less likely to transmit HIV-1 to their children, possessed better cellular markers of disease progression (i.e. CD4 and CD8 counts and percentages), and were more likely to become long term non-progressors than women for whom the protease gene was amplifiable.; We have hypothesized that these women are infected with virus which is somehow less virulent than that infecting women with amplifiable virus, and that this virulence is associated with viral factors because the group was isolated based on our inability to amplify a gene with primers in the region of it.; Sequence analysis has shown that significant variability of p7, p1 and p6 genes exists in active motifs from both amplifiers and non-amplifiers in the study group. These changes are significantly more likely to be found in the "PEPTAPPA" motif of p6gag, and the "LWQRPLVT" motif of p6pol. We have also seen that there were significantly more changes in proline residues located in the p1 protein as compared to amplifiers. Though these changes may not be the whole answer as to why the virus in these women appears less pathogenic, they may certainly be a part of it.; Finally, we have shown that in a few individuals at least, our inability to amplify the protease gene is associated with a significantly decreased ability to grow and produce progeny in cell culture, a finding which adds credibility to our hypothesis that viral genetic factors play an important role in the pathogenicity and transmissibility of the HIV-1 virus.