See instmctions): In this continuation application/progress report for an R37 MERIT Award, the progress on the two major specific aims is reviewed. The overall goal of the work is to use HIV-1 sequence diversity to examine the biological determinants of transmission and pathogenesis. These studies will inform our understanding of the transmission and disease processes.
The first aim covering the study of samples from an HIV-1 vertical transmission cohort Is nearing completion. A major feature of the remaining work is to create molecular clones of the env genes from maternal and infant viral populations to test the rote of autologous neutralizing antibodies in vertical transmission. This work will test the hypothesis that a neutralization escape variant is responsible for vertical transmission. In addition, these studies will reveal the complexity of the virus in vertical transmission and provide reagents to study other biological properties of the transmitted virus.
The second aim on horizontal transmission is still awaiting the availability of samples from people in acute infection from southem Braal. Given progress in the field this aim is now refined to focus on the question of the relative fitness of subtype B and subtype C viruses Involved in acute infection and coclrculating in the same population. This analysis is designed to address the question of whether differences in relative viral fitness play a role in the subtype B and C epidemics. Studies in viral diversity are in part framed by the technology available to study that diversity. Two important and complementary technologies for studying diversity are the heteroduplex tracking assay (HTA) and the single genome amplification (SGA) approach. The new technology of deep sequencing has not been approriately applied to the study of viral diversity due to intrinsic problems of PCR resampling. A new strategy will be applied to overcome this problem to allow the accurate use of this new technology to study viral diversity using HIV as the test case This will provide a third complementary approach to the study of viral diversity. The application of these strategies in ways that could inform clinical care will also be explored. Finally, collaborative opportunities have been developed to study viral evolution in a humanized mouse model and under the influence of AP0BEC3G/F and will be continued.
(See Instmctions): HIV sequence diversity is a rich source of biological infonnation about the selective pressures placed on the virus and changes in virus-host interactions. We are using viral sequence diversity to explore questions important for vertical and horizontal transmission and the evolution of pathogenic variants after transmission. In addition, we continue to develop new technologies to derive more information from complex viral populations. These efforts shed light on important virologic features of transmission and evolution. PROJECT/PERFOI^MANCE SiTE(S) (if addifional space is needed, use Project/Perfonnance Site Fonnat Page)
|Joseph, Sarah B; Arrildt, Kathryn T; Sturdevant, Christa B et al. (2015) HIV-1 target cells in the CNS. J Neurovirol 21:276-89|
|Joseph, Sarah B; Arrildt, Kathryn T; Swanstrom, Adrienne E et al. (2014) Quantification of entry phenotypes of macrophage-tropic HIV-1 across a wide range of CD4 densities. J Virol 88:1858-69|
|Jabara, Cassandra B; Hu, Fengyu; Mollan, Katie R et al. (2014) Hepatitis C Virus (HCV) NS3 sequence diversity and antiviral resistance-associated variant frequency in HCV/HIV coinfection. Antimicrob Agents Chemother 58:6079-92|
|Keys, Jessica R; Leone, Peter A; Eron, Joseph J et al. (2014) Large scale screening of human sera for HCV RNA and GBV-C RNA. J Med Virol 86:473-7|
|Russell, Elizabeth S; Ojeda, Suany; Fouda, Genevieve G et al. (2013) Short communication: HIV type 1 subtype C variants transmitted through the bottleneck of breastfeeding are sensitive to new generation broadly neutralizing antibodies directed against quaternary and CD4-binding site epitopes. AIDS Res Hum Retroviruses 29:511-5|
|Pollom, Elizabeth; Dang, Kristen K; Potter, E Lake et al. (2013) Comparison of SIV and HIV-1 genomic RNA structures reveals impact of sequence evolution on conserved and non-conserved structural motifs. PLoS Pathog 9:e1003294|
|Arrildt, Kathryn Twigg; Joseph, Sarah Beth; Swanstrom, Ronald (2012) The HIV-1 env protein: a coat of many colors. Curr HIV/AIDS Rep 9:52-63|
|Valley-Omar, Ziyaad; Sibeko, Sengeziwe; Anderson, Jeffrey et al. (2012) CAPRISA 004 tenofovir microbicide trial: no impact of tenofovir gel on the HIV transmission bottleneck. J Infect Dis 206:35-40|
|Schnell, Gretja; Joseph, Sarah; Spudich, Serena et al. (2011) HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog 7:e1002286|
|Russell, Elizabeth S; Kwiek, Jesse J; Keys, Jessica et al. (2011) The genetic bottleneck in vertical transmission of subtype C HIV-1 is not driven by selection of especially neutralization-resistant virus from the maternal viral population. J Virol 85:8253-62|
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