Molecular Virology & Pathogenesis
The Department of Molecular Virology and Pathogenesis (DMVP) focuses on the use of molecular techniques to characterize host and viral genetic characteristics as they apply to prevalent and incident HIV infections in vaccine and natural history cohorts. They also work to:
- Characterize the genetic diversity of the HIV epidemic, particularly in geographic areas of interest for vaccine development.
- Describe the genetic evolution of HIV over the natural history of infection and in response to targeted therapies.
- Investigate the effect of human genetic diversity on host-pathogen interaction with the goal of identifying variants within human genes that may be correlated with disease outcomes. Outcomes of interest include the natural history of HIV infection with regard to viral control and disease progression, also clinical response to antiretroviral therapy and vaccination.
- Leverage host gene expression profiling to identify correlates of productive responses to vaccination, drug intervention and differential outcomes of disease.
Current Research
- Genetically characterizing breakthrough infections from RV144, the phase III trial of an HIV prime-boost vaccine combination in Thailand, and investigating the effect of human genetic variation on vaccine response.
- Genotypically characterizing the HIV-1 outbreak in Nigeria, Bulgaria, and the HIV epidemic in IDU in Afghanistan.
- Characterizing human genetic variation in genes involved with host restriction (e.g., co-receptors, apobec, trim5, tetherins), innate immunity (e.g., KIR, FcGamma receptors), and adaptive immunity (e.g., HLA) in world populations participating in HIV-vaccine trials.
- Developing novel technologies for high-throughput, high-resolution genotyping of genes of interest.
- Developing a new version of MHA genotyping tool, Version 3, for HIV-1 subtype A, C, D to accommodate the dynamic of HIV-1 diversity in East Africa.
- Identification of host genetic elements associated with differences in HIV acquisition and progression.
- Collaborate with the Vaccine Immunomonitoring Consortium of the Centers for AIDS Vaccine Collaboration to generate HIV-1 envelope pseudoviruses for neutralization assay.
- Generating primary-isolate infectious molecular clones (IMCs) from HIV+ individuals representing subtypes A, B, C, D, CRF01_AE, and CRF02_AG. Modifying these IMCs to express the Renilla luciferase reporter gene for use in enhanced antibody neutralization assays.
- Collaborating with the NIH Department of AIDS to genetically characterize a standard panel of HIV isolates for use as reference reagents.
- Sequencing and analysis of breakthrough viruses from the STEP HIV vaccine trial (HVTN 502) using full-length, single genome amplification.
- Immunologic and virologic events in early HIV infection predict subsequent rate of progression.
- CCL3L1 and HIV/AIDS susceptibility
- The Duffy antigen receptor for chemokines null promoter variant does not influence HIV-1 acquisition or disease progression.
- Studying the effects and mechanisms-of-action of steroids on the expression of HIV-1 co-receptors CXCR4 and CCR5.
- Elucidating the molecular circuitry involved in differential expression of the HIV-1-binding receptor, DC-SIGN, during dendritic cell maturation.
- Identifying differential expression genes associated with immunoproteasome processing of MHC peptides and protection in persons receiving the RTS,S malaria vaccine.
- Identifying differential expression of genes associated with the impact of co-infection with SIV and malaria in a non-human primate model on both the pathogenesis of both diseases and on vaccination and outcome with and DNA subunit vaccine for SIV.
Highlights & Publications
- Using single genome amplification techniques, DMVP scientists compared HIV sequences in breakthrough infections in STEP HIV vaccine trial participants to the vaccine sequence. The results demonstrated that breakthrough viruses from vaccines had diverged further from the STEP vaccine sequence than viruses from placebo recipients.
- Sequencing HIV-1 strains infecting a cohort of men having sex with men (MSM) and female sex workers (FSW) in Kenya, DMVP scientists identified a close social network with extended chains of transmission and a high proportion of dual and recombinant infections, describing eight novel inter-subtype recombinant forms.
- Host genetics investigators studied host restriction, killer immunoglobulin-like receptor (KIR), and HLA genes among Ugandan and Tanzanian populations, demonstrating the presence of a major East African cluster, which is characterized by one of the largest degrees of genetic diversity worldwide.
- Using gene expression profiling genes associated with immunoproteasome processing of MHC peptides were demonstrated to differentiate persons protected by a subunit vaccine for malaria prior to challenge and after the third round of vaccination.
Future Work
- Molecular characterization of HIV-1 infections in DoD to support Defense Health Program.
- Studying viral diversity across anatomic compartments in acute HIV infection isolates generated by RV254, an acute infection protocol being conducted in conjunction with the Thai Red Cross.
- Developing new techniques for rapid analysis of HIV-1 viruses regarding viral evolution and the diversity of viral sequences in response to immune pressure exerted by host and/or vaccination.
- Characterize genetic polymorphisms in genes controlling host restriction, innate and adaptive Immunity, and their influence on HIV acquisition and early control of HIV infections in high-risk cohorts of adults in East Africa and Southeast Asia.
- Cohort Development to Determine Genetic Mechanisms of Protection from HIV-1 Acquisition Among Persons At Risk for HIV Infection.