Sex and age-matched wild-type and TCR transgenic mice were infected with cytomegalovirus (CMV) at 6 months of age and followed for 12 additional months to examine aging of the immune system. It was found that viral infection of C57Bl/6 mice resulted in accelerated aging of the immune system as shown by a loss of CD8(+)28(+) cells and an accumulation of KLRG1(+) T cells. CMV infection of OT-1 transgenic mice had no influence on immune aging of these mice which nonetheless demonstrated an accumulation of CD8(+)28(-) and KLRG1(+) T cells with time. CD4(+) T cells were unaffected in either strain of mice. Thus, immunological aging was found to be due to both cell-intrinsic and cell-extrinsic factors. Persistent viral infections may accelerate immunological aging but consideration must be given to individual variation in the aging process.
Most antiretroviral drugs currently in use to treat an HIV-1 infection are chemically synthesized and lead to the development of viral resistance, as well as cause severe toxicities. However, a largely unexplored source for HIV-1 drug discovery is endophytic fungi that live in a symbiotic relationship with plants. These fungi produce biologically active secondary metabolites, which are natural products that are beneficial to the host. We prepared several hundred extracts from endophytic fungi of desert plants and evaluated the inhibitory effects on HIV-1 replication of those extracts that showed less than 30% cytotoxicity in T-lymphocytes. Those extracts that inhibited viral replication were fractionated in order to isolate the compounds responsible for activity. Multiple rounds of fractionation and antiviral evaluation lead to the identification of four compounds, which almost completely impede HIV-1 replication. These studies demonstrate that metabolites from endophytic fungi of desert plants can serve as a viable source for identifying potent inhibitors of HIV-1 replication.
HIV-1 exists as a genetically heterogeneous population within infected individuals and in infected population. Genetic variability or viral heterogeneity plays an important role in transmission, pathogenesis, immune response, disease progression and therapy as well as is the most effective way for the virus to evade the host immune response and persists in infected individuals. We have used HIV-1 infected motherinfant pairs as a transmitter-recipient model to elucidate the role of the molecular and biological properties of HIV-1 associated with transmission and pathogenesis. HIV-1 sequences derived from infected mothers were more heterogeneous than their younger infected infants’ HIV-1 sequences. However, the infants’ HIV-1 sequences diversified as they grew older. HIV-1 infants’ sequences were different from each other but similar or closer to their mother’s sequences. We found that the minor genotypes of HIV-1 found in mothers were transmitted to their infants, which was initially maintained as a homogeneous population in infants and diversified as the infants grew older. In addition, the phenotype of these minor geno types was macrophage-tropic, nonsyncytium inducing (NSI) referred as R5 HIV-1. We also analyzed several other regions of HIV-1 genome, including env, gag p17 and NC, pol RT, tat, rev, vif, vpr, vpu and nef infected mother-infant pairs and found that there was a high functional conservation of these genes. These findings suggested that HIV-1 heterogenity plays an important role in vertical transmission and pathogenesis. The properties of transmitted viruses and those that are associated with disease progression should be targeted for the development of new strategies for prevention and treatment of HIV-1 infection. Research should focus utilizing these findings in the development of better strategies for prevention and treatment of HIV-1.
