Perinatal infection has provided a valuable model for studying HIV-1 evolution and disease progression. However, most studies on disease progression and viral evolution have focused on infected adults of developed countries infected by Clade B virus. Very little is known about disease progression associated with non-Clade B viruses, especially in children in developing countries with an HIV-1 epidemic. An example is Zambia, a sub-Saharan African nation located in the I-IIV-1 belt, with a very high incidence of HIV-1 infection. Our preliminary studies in women of childbearing age have shown an HIV-1 seroprevalence of about 35 percent. HIV-1 isolates from Zambia belong to the non-Clade B subgroups. In the absence of anti-retroviral therapy, many of the babies born to these mothers will be infected by HIV-I. The objective of the proposed work is to understand HIV-1 evolution in an epidemic region in the absence of selection pressure due to anti-retroviral therapy, so that strategies can be developed to block their replication and transmission. Our immediate goal is to longitudinally isolate and characterize Clade C viruses from infants infected by HIV-1 perinatally in Zambia. This proposal will make use of an ongoing study on the transmission of Kaposi's sarcoma :associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) from Zambia. Using the developed infrastructure at the University Teaching Hospital in Zambia, its ongoing recruitment of mother/infant pairs at delivery and at follow-ups, we will longitudinally collect non-Clade B local viral isolates for this project. The specific aims are: 1) to isolate Zambian non-Clade B HIV-1 samples from infected infants longitudinally, and study their biological properties and host cell tropism; 2) to characterize patterns of genetic diversity and sequence evolution of longitudinal HIV-1 isolates from infected infants; 3) to integrate the virological and genetic analyses of longitudinal HIV-1 isolates with clinical disease manifestations. This study will generate important information about the evolution of Clade C strains in Zambia.