Research interests

HIV: Structure-function and Viral Fitness

Overall focus: Investigating the role of HIV envelope in viral fitness.

Viral fitness is defined as the ability of Human Immunodeficiency virus to replicate in a given environment.

The very first viral contact with host cells is mediated by the envelope protein that occurs as spikes on the viral surface. Envelope comprising of gp120 and gp41binds to CD4 and CCR5 receptors on T lymphocytes and undergoes a series of conformational changes that allows the fusion of viral and plasma membranes, culminating in the release of viral RNA into the cytoplasm. The HIV lifecycle thus involves entry, reverse transcription of the viral RNA, integration into the chromosomal DNA, transcription, translation of viral proteins, viral particle formation and budding. Dr Woodman’s laboratory focuses on the entry process and its impact on the ability of HIV to complete its life cycle efficiently. More specifically, Dr Woodman’s research focuses on elucidating the role and impact of envelope function on the ability of HIV to replicate within a given environment. The two major research thrusts are: 1) identifying Envelope functional determinates that impact HIV fitness and 2) the impact of Envelope N-glycosylation on HIV transmission. Recently, her group has also extended their interest into understanding the mechanism whereby bacteria associated with Bacterial Vaginosis increases the risk of HIV acquisition.

 

HIV-1 subtype C Envelope functional determinants as targets for drug and vaccine design

Sites within structurally constrained regions of Envelope that affect viral replication are potential targets for drug and vaccine design, especially as they are more unlikely to mutate and evade therapeutics and immune responses. This study investigates individuals that are dual infected with two HIV phylogenetically distinct variants as a model for identifying these sites within Envelope. These dual infected individuals usually have rapid disease progression and it is hypothesised that this is because the two distinct variants can rapidly evolve to gain replication fitness by exchanging regions of env via recombination generating natural chimeric viruses with potential differences in fitness. By identifying sites associated with enhanced fitness, this project will identify determinants essential for viral propagation, prime candidates for drug and vaccine targets. Moreover, this study will also investigate the mechanistic relationship between the function of structurally constrained sites and their impact on viral replication. Given the limited research focus on the structure and function of subtype C Env, this project will advance current knowledge on subtype C infections.

 

N-glycosylation patterns of gp120 involved in HIV transmission

As vaccines and microbicides are designed to target transmitted variants this study aims to elucidate the mechanism whereby HIV variants are able to cross the genital epithelium and infect CD4 T lymphocytes. In eight out of 10 transmission events, a single HIV infectious unit results in productive infection likely due to an intact genital epithelium barrier. Transmitted variants are enriched for env sequences with shorter variable loops and fewer N-glycan sites than variants from chronically infected individuals. This suggests that transmission might be dependent on the presence or absence of specific N-glycan sites and that lectins (carbohydrate binding proteins) expressed by the genital mucosal cellular milieu might be involved in HIV infection. Dendritic cells are located at the rectal and genital mucosa and express a lectin (DC-SIGN) that has been shown to bind to gp120 and mediate HIV trans-infection of CD4+ T cells. Therefore, DC-SIGN might selectively bind to variants depending on the presence or absence of specific N-glycan sites on gp120. This study tests the hypothesis that HIV variants are successfully transmitted because they carry an optimal arrangement of N-glycans that facilitate their interactions by dendritic cells through binding to DC-SIGN (or an as yet unidentified lectin), favouring transmission of select variants.

 

Relationship between Bacterial vaginosis (BV) and HIV-1 infection

This study aims to determine the mechanism whereby BV increases HIV-1 acquisition.

The prevalence of BV in sub-Saharan Africa ranged from 30-40%, with female sex workers and HIV positive women with the highest prevalence. BV is associated with HIV infection, suggesting that the presence of genital tract anaerobic bacterial infection enhances HIV infection. The mechanism driving this association remains unknown. Identification of the causative agent could provide a novel therapeutic target for the prevention of HIV transmission in the presence of BV. It was recently shown that sialidase production increased with the onset of BV and that sialidases have been identified as a virulence factor in the infection of many bacteria including Gardnerella vaginalis, Bacteroides spp., Prevotella spp., and Mobilucus spp., bacterial pathogens associated with BV. It is possible that desialylation of Envelope N glycans could improve the binding of Envelope to target cells and thus enhance HIV transmission. This study aims to investigate the role of bacterial sialidases in HIV infection as well as identify novel compound(s) secreted by BV-associated bacteria that could enhance HIV infection using a proteomics approach.

 

Lab members

Shatha Omar (PhD student)

Evelyn Ngwa (PhD student)

Bahiah Meyer (MSc student)

Riley Traviss (MSc student)

Bianca Abrahams (MSc student)

 

Select Publications

  1. Woodman ZL, Schwager SL, Redelinghuys P, Carmona AK, Ehlers MR, Sturrock ED. The N domain of somatic angiotensin-converting enzyme negatively regulates ectodomain shedding and catalytic activity. Biochem J. 2005 Aug 1;389(Pt 3):739-44.
  2. Irina V. Balyasnikova, Zenda L. Woodman, Ronald F. Albrecht II, Ramanathan Natesh, K Ravi Acharya, Edward D. Sturrock and Sergei M. Danilov.The Localization of an N-domain Region of Angiotensin-Converting Enzyme Involved in the Regulation of Ectodomain Shedding using Monoclonal Antibodies J Proteome Res. 2005 Mar-Apr;4(2):258-67
  3. Bajaj, BG, Verma SC, Lan K, Cotter MA, Woodman ZL, Robertson ES KSHV encoded LANA upregulates Pim-1 and is a substrate for its kinase activity. Virology. 2006 Jul 20;351(1):18-28.
  4. Chopera. D.R., Woodman ZL,  Mlotshwa M, Martin D.P., Seoighe C., Treurnicht F., Assis de Rosa D., Hide W., Mlisana K., Abdool Karim S, Gray C.M., Williamson C. Transmission of HIV-1 CTL escape variants provides HLA-mismatched recipients with a survival advantage Plos Pathogens 2008 Mar 21;4(3):e1000033
  5. Nobubelo K. Ngandu, Konrad Scheffler, Penny Moore, Darren Martin, Zenda Woodman and Cathal Seoighe Purifying selection affecting synonymous sites reveals functional nucleotide motifs in HIV-1. Virology Journal 2008 5:160 Impact factor:
  6. Woodman ZL & Williamson C HIV molecular epidemiology: HIV transmission and adaptation in humans. Curr Opin HIV AIDS. 2009 Jul;4(4):247-52. Review
  7. F.K. Treurnicht, C. Seoighe, D.P. Martin, N. Wood, M-R. Abrahams, D. Assis de Rosa, H. Bredell, Z. Woodman, W. Hide, K. Mlisana, S Abdool Karim, C.M. Gray, C. Williamson Site specific differences in amino acid frequencies within HIV-1 subtype C proteins expressed during early and chronic infections Virology 2010 Jan 20;396(2):213-25.
  8. Mandla Mlotshwa, Catherine Riou, Denis Chopera, Debra de Assis Rosa, Roman Ntale2, Florette Treunicht, Zenda Woodman, Lise Werner, Francois van Loggerenberg, Koleka Mlisana, Salim Abdool Karim, Carolyn Williamson, Clive M Gray and the CAPRISA 7 002 study team Fluidity of HIV-1 Specific T Cell Responses during Acute and 1 Early Subtype C HIV-1 Infection and Associations with Early Disease Progression. 2010. J Virol. 2010 Nov; 84(22):12018-29. Epub 2010 Sep 8.
  9. Zenda Woodman, Koleka Mlisane, Florette Treurnicht , Ruwayida Thebus, Melissa Abrahams, , Abdool Karim and Carolyn Williamson Decreased Incidence of Dual Infections in South African Subtype C-Infected Women Compared to a Cohort Ten Years Earlier. AIDS Research and Retroviruses. 2011 Nov;27(11):1167-72
  10. Andile Nofemela, Gama Bandawe, Ruwayhida Thebus, Jinny Marais, Natasha Wood, Leonard Maboko, Michael Hoelscher, Zenda Woodman, Carolyn Williamson Defining the HIV-1 transmission genetic bottleneck in a region with multiple circulating subtypes and recombinant forms 2011 Virology Jul 5;415(2):107-13.
  11. D.R. Chopera1, M. Mlotshwa2, Z. Woodman3,K. Mlisana4, D. de Assis Rosa2, D.P. Martin1, S. Abdool Karim4, C. Gray2, C. Williamson1 and the CAPRISA 002 Study Team Virological and Immunological Factors Associated with HIV-1 Differential Disease Progression in HLA-B*5801 Positive Individuals 2011 J Virol. Jul;85(14):7070-80.
  12. Roberts L, Passmore JA, Mlisana K, Williamson C, Little F, Bebell LM, Walzl G, Abrahams MR, Woodman Z, Abdool Karim Q, Abdool Karim SS. Genital tract inflammation during early HIV-1 infection predicts higher plasma viral load set point in women. J Infect Dis. 2012 Jan 15;205(2):194-203.
  13. Chopera DR, Cotton LA, Zawaira A, Mann JK, Ngandu NK, Ntale R, Carlson JM, Mlisana K, Woodman Z, de Assis Rosa D, Martin E, Miura T, Pereyra F, Walker BD, Gray CM, Martin DP, Ndung'u T, Brockman MA, Abdool Karim S, Brumme ZL, Williamson C; the CAPRISA 002 Study Team. Intersubtype differences in the effect of a rare p24 Gag mutation on HIV-1 replicative fitness. J Virol. 2012 J Virol. 2012 Dec;86(24):13423-33.
  14. Ntale RS, Chopera DR, Ngandu NK, Assis de Rosa D, Zembe L, Gamieldien H, Mlotshwa M, Werner L, Woodman Z, Mlisana K, Abdool Karim S, Gray CM, Williamson C; the CAPRISA 002 Study Team. Temporal Association of HLA-B*81:01- and HLA-B*39:10-Mediated HIV-1 p24 Sequence Evolution with Disease Progression. J Virol. 2012 Nov;86(22):12013-12024.
  15. Daniel J. Sheward, Roman Ntale, Nigel J. Garrett, Zenda L. Woodman, Salim S. Abdool Karim, and Carolyn Williamson HIV-1 superinfection resembles primary infection  J Infect Dis. 2015 Mar 9. pii: jiv136. [Epub ahead of print]
  16. Gordon K; Omar S; Nofemela A; Bandawe  G; Williamson C; Woodman Z A recombinant variant with increased Envelope entry efficiency emerged during early infection of an HIV-1 subtype C dual infected rapid progressor. AIDS Research and Human Retroviruses 2015 Apr 23. [Epub ahead of print]
  17. Nofemela A, Selhorst P, Bandawe G, Marais J, Maboko L, Hoelscher M, Williamson C, Woodman Z Phenotypic characterisation of Human Immunodeficiency Virus type 1 Envelope entry efficiency of transmitted/founder variants circulating in Mbeya, Tanzania. Med Res Arch 2015 Oct 8-18 2(2)
  18. Woodman ZL Can one size fit all? Approach to Bacterial Vaginosis in sub-Saharan Africa. Annals of Clinical Microbiology and Antimicrobials 2016 11;15:16.