RESEARCH INTERESTS: Transmission, evolution and pathogenesis of HIV-1 subtype C in maternal to infant pairs from Africa. Mechanisms of endogenous viral silencing through epigenetic modifications of histones.

Subtype C HIV-1 infections continue to increase in the developing world, particularly in sub-Saharan Africa, India and China. The primary routes of HIV-1 infection in developing nations are unprotected heterosexual contact, and mother to child transmission. For example, in the longitudinal cohort of women delivering at the University Teaching Hospital, Lusaka, Zambia (the source of a number of our samples), the seroprevalence was 30%. Such untreated mothers transmit HIV-1 to their infants (in utero or intrapartum) in approximately 30% of deliveries, and of the remaining 70% of infants who escape initial infection, 15% or more become infected through breast-feeding. We focus on mother to child transmission because these pairs represent one of only a few instances where the donor and recipient as well as the direction and timing of transmission are known. For evolutionary studies these pairs provide one of the most critical bits of data, the starting point.

Transmission of HIV-1 is a function of the envelope glycoprotein (Env) that mediates receptor and coreceptor interactions leading to fusion of the viral membrane with that of a target cell. We study the evolution of Env in order to define the determinants in this protein that contribute to mother to child transmission, immune evasion, and disease pathogenesis in children. HIV-1 evolves through the generation of tremendous diversity due to the lack of proof-reading activity in its reverse-transcriptase/replicase. On average each genome will have at least one mutation relative to the template RNA, and the number of particles in an untreated person can be greater than 109/ml in acute phase. This creates a swarm of nearly identical but distinct individuals, a ‘quasispecies’, and lends incredible plasticity to the virus for adaptation to changing environments and selective pressures. Fitness is measure of an organism’s ability to survive/persist in a given environment (generally implies the production of progeny). Recent data suggest a link between HIV- Env and viral fitness and between fitness and disease progression, but these concepts have not been tested with regard to transmission or in longitudinal samples from transmission pairs. Thus, we are evaluating whether there are links between fitness and virus transmission or disease progression in children where the donor is known and the timing of transmission is known or can be approximated. We utilize a combination of genetic, phylogenetic, molecular, immunological and biochemical approaches at the in vitro and ex vivo level to investigate these potential relationships.

Our hypotheses are: a.) HIV-1 fitness evolves in patients coordinate with longitudinally acquired changes in Env genotype and phenotype. b.) Fitness is directly correlated with transmissibility and pathogenicity of HIV-1.

Our Aims are: 1.) To determine whether the viral fitness of maternal (donor) viruses correlates with transmission to infants; 2.) To determine whether high fitness transmitter mothers transmit high fitness viruses; 3.) To investigate whether infants that initially acquire high fitness virus(es) progress more rapidly than those who acquire lower fitness virus(es); 4.) To define molecular determinants of replication or transmission fitness gains or losses.

Long-term aim: Our ultimate goal is to refine the current understanding of the determinants of HIV-1 transmission evolution and disease and to utilize this understanding to design better treatments or preventatives targeting the Env glycoprotein that limit or direct viral evolution in directions that lead to lasting protection.

In our most recent findings we have used Env PCR products from Zambian mother-infant pairs to characterize the longitudinal evolution of HIV-1 Env at the genetic level for the life of infected children. We have identified rapid and slow progressor children, segregated by the clinical outcome of HIV-1 infection, and we have identified a small number of acute seroconverters pairs. For each group viral isolates or Env clones be created and the relationships between Env length and glycosylation as well as sensitivity to neutralizing antibody have been tested. Our current focus is on biological and biochemical characterization of the Env glycoprotein in functional and quantitative assays, as well as the implementation of replication fitness determinations by ex vivo dual infection competitions. We are also developing organotypic culture systems to evaluate viral ‘transmission fitness’ across mucosal barriers so as to model natural targets of initial infection and identify the viral determinants of transmissibility. Other projects in the lab focus on the epigenomic mechanisms of endogenous retroviral silencing and the role of epigenetics in the generation of viral latency for chronic infections.

Publications:

1) Fultz, P. N., Su, L., May, P., and West, J.T. 1997. Isolation of a Sooty Mangabey simian T-cell leukemia virus type I  [STLV-I(sm)] and characterization of a mangabey T-cell line coinfected with STLV-1(sm and simian immunodeficiency virus SIVsmmPBj14. Virology

235: 271-285.

2) Salzwedel, K., West, J.T., Mulligan, M.J., and Hunter, E. 1998. Retention of the HIV-1 envelope glycoprotein in the endoplasmic reticulum does not redirect virus assembly from the plasma membrane. J. Virol. 72(9):7523-7531.

3) Salzwedel, K., West, J.T., and Hunter, E. 1999. A conserved tryptophan-rich motif in the membrane-proximal region of the human immunodeficiency virus type 1 gp41 ectodomain is important for Env-meidated fusion and virus infectivity. J. Virol. 73(3): 2469-2480.

4)    West J.T., Johnston, P.B., Dubay, S.R., and Hunter, E. 2001. Mutations within the putative membrane-spanning domain of the SIV transmembrane glycoprotein define the minimal requirements for fusion, incorporation and infectivity. J. Virol. 75(20): 96019612.

5)    West J.T., Weldon, S.K., Lin, X., Wyss, S., Thali, M., and Hunter, E. 2001. Mutation of the dominant endocytosis motif in HIV-1 gp41 can complement matrix mutations without increasing Env incorporation. J. Virol. 76(7): 3338-3349.

6) Brayfield, B., Phiri, S., Kankasa, C., Muyanga, J., Mantina, H., Kwenda, G., West, J.T., Bhat, G., Marx, D., Klaskala, W., Mitchell, C., and Wood, C.  2002. Postnatal human herpesvirus-8 and human immunodeficiency virus-1 infection in mothers and infants from Zambia.  J. Inf. Dis. 187:559-68.

7) Lin, X., Derdeyn, C.A., Blumenthal, R., West, J.T., and Hunter, E. 2002. Progressive truncations C-terminal to the membrane-spanning domain of SIV Env reduce fusogenicity and increase concentration dependence of Env for fusion.  J. Virol. 77: 7067-7077.

8) Ghosh, M.K., Kuhn, L., West, J.T., Semrau, K., Decker, D., Thea, D.M., Aldrovandi,

G.M. 2003. Quantitation of Human Immunodeficiency Virus Type 1 in Breast Milk. J Clin Microbiol. 41(6):2465-2470.

9) Burkala, E., West, J.T., Petito, C., and Wood, C. 2003. “The choroid plexus and viral entry into the brain” The Neurology of AIDS. Gendelman, Grant, Everall, Lipton & Swindells, eds.; Oxford University Press.

10) West, J. T. and C. Wood. 2003 Role of the HHV-8/KSHV transcriptional regulator Orf50 in control of gene expression. Oncogene. 22(33):5150-63.

11) Brayfield, B.P., Kankasa, C., West, J.T., Muyanga, J., Bhat, G., Klaskala, W., Mitchell, C.D., Wood, C. 2004. Distribution of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 in maternal saliva and breast milk in Zambia: implications for transmission. J Infect Dis. 189(12):2260-70.

12) Wang, J., Zhang, J., Zhang, L., Harrington Jr., W., West, J.T. and Wood, C. 2005. Modulation of human herpesvirus-8/Kaposi’s sarcoma-associated herpesvirus RTA transactivation by interferon regulatory factor 7. J Virol. 79(4):2420-31

13) Klaskala, W., Brayfield, B.P., Kankasa, C., Bhat, G., West, J.T., Mitchell C.D., and Wood, C. 2005. Epidemiological characteristics of human herpesvirus-8 infection in a large population group of Zambian antenatal women. J Med Virol. 75(1):93-100

14) Burkala E.J., He J., West J.T., Wood C., Petito C.K. 2005. Compartmentalization of HIV1 in the central nervous system: role of the choroid plexus. AIDS. 19(7):675-84.

15) Zhang, H., Hoffmann, F., He, J., He, X., Kankasa, C., Ruprecht, R., West, J.T., Orti, G., and Wood, C. 2005. Evolution of subtype C HIV-1 Env in a slowly progressing Zambian infant. Retrovirology 2:67.

16) St. Lawrence, J.S., Klaskala, W., Kankasa C. West, J.T.,  Mitchell, C.D. and  Wood, C. 2006. Factors associated with HIV prevalence in a pre-partum cohort of Zambian women. (IJSA 05437- Accepted for publication 5/06) Int J STD AIDS. 17.

17)   Zhang, H., Hoffmann, F.G., He, J., He, X.,  Kankasa, C., West, J.T., Mitchell, C.D., Orti, G., and C. Wood, C. 2006.Characterization of HIV-1 subtype C envelope glycoproteins from perinatally infected children with different courses of disease. (Submitted 24 May 2006, Retrovirology)

18)Minhas, V., Crabtree, K.L., M’soka, T.J., Phiri, S., Kankasa, C., West, J.T., Mitchell, C.D., and Wood, C. 2006. Early Childhood Infection by Kaposi’s Sarcoma Associated Herpesvirus in Zambia and the Role of HIV-1 as a Risk Factor. (Submitted 19 May 2006 J Inf Dis)

Return to Faculty Page

Return to Home Page

Last edited 08/21/08 Please send comments, questions, or error reports to cheryl-murphy@ouhsc.edu Copyright © 2008 The Board of Regents of the University of Oklahoma, All Rights Reserved University of Oklahoma Disclaimers

.