Browsing by Author "Chopera, Denis Rutendo."

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Brief report: selection of HIV-1 variants with higher transmission potential by 1% tenofovir gel microbicide.
(Wolters Kluwer Health., 2017) Ngandu, Nobubelo K.; Carlson, Jonathan M.; Chopera, Denis Rutendo.; Ndabambi, Nonkululeko.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.
Abstract available in pdf.
Early evolution of HLA-associated escape mutations in variable Gag proteins predicts CD4+ decline in HIV-1 subtype C infected women.
(Wolters Kluwer Health., 2017) Chopera, Denis Rutendo.; Ntale, Roman.; Ndabambi, Nonkululeko.; Garrett, Nigel Joel.; Gray, Clive M.; Matten, David.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.
Abstract available in pdf.
Fluidity of HIV-1-Specific T-Cell Responses during Acute and Early Subtype C HIV-1 Infection and Associations with Early Disease Progression.
(American Society for Microbiology, 2010) Mlotshwa, Mandla.; Riou, Catherine.; Chopera, Denis Rutendo.; de Assis Rosa, Debra.; Ntale, Roman.; Treurnicht, Florette K.; Woodman, Zenda.; Werner, Lise.; van Loggerenberg, Francois.; Mlisana, Koleka Patience.; Williamson, Carolyn.; Gray, Clive M.; Abdool Karim, Salim Safurdeen.
Deciphering immune events during early stages of human immunodeficiency virus type 1 (HIV-1) infection is critical for understanding the course of disease. We characterized the hierarchy of HIV-1-specific T-cell gamma interferon (IFN-y) enzyme-linked immunospot (ELISPOT) assay responses during acute subtype C infection in 53 individuals and associated temporal patterns of responses with disease progression in the first 12 months. There was a diverse pattern of T-cell recognition across the proteome, with the recognition of Nef being immunodominant as early as 3 weeks postinfection. Over the first 6 months, we found that there was a 23% chance of an increased response to Nef for every week postinfection (P = 0.0024), followed by a nonsignificant increase to Pol (4.6%) and Gag (3.2%). Responses to Env and regulatory proteins appeared to remain stable. Three temporal patterns of HIV-specific T-cell responses could be distinguished: persistent, lost, or new. The proportion of persistent T-cell responses was significantly lower (P = 0.0037) in individuals defined as rapid progressors than in those progressing slowly and who controlled viremia. Almost 90% of lost T-cell responses were coincidental with autologous viral epitope escape. Regression analysis between the time to fixed viral escape and lost T-cell responses (r = 0.61; P = 0.019) showed a mean delay of 14 weeks after viral escape. Collectively, T-cell epitope recognition is not a static event, and temporal patterns of IFN-y-based responses exist. This is due partly to viral sequence variation but also to the recognition of invariant viral epitopes that leads to waves of persistent T-cell immunity, which appears to associate with slower disease progression in the first year of infection.
Intersubtype differences in the effect of a rare p24 Gag mutation on HIV-1 replicative fitness.
(American Society for Microbiology., 2012) Chopera, Denis Rutendo.; Cotton, Laura A.; Zawaira, Alexander.; Mann, Jaclyn Kelly.; Ngandu, Nobubelo K.; Ntale, Roman.; Carlson, Jonathan M.; Mlisana, Koleka Patience.; Woodman, Zenda.; de Assis Rosa, Debra.; Martin, Eric.; Miura, Toshiyuki.; Pereyra, Florencia.; Walker, Bruce D.; Gray, Clive M.; Martin, Darren Patrick.; Ndung'u, Peter Thumbi.; Brockman, Mark A.; Abdool Karim, Salim Safurdeen.; Brumme, Zabrina L.; Williamson, Carolyn.
Certain immune-driven mutations in HIV-1, such as those arising in p24Gag, decrease viral replicative capacity. However, the intersubtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24Gag M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (P 0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles (P<0.01). In contrast, in subtype C, it is a relatively common minor polymorphic variant (10 to 15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24Gag codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro replicative defects, while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of cytotoxic-T-lymphocyte-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness.
Killer-cell Immunoglobulin-like Receptor (KIR) gene profiles modify HIV disease course, not HIV acquisition in South African women.
(BioMed Central., 2016) Naranbhai, Vivek.; de Assis Rosa, Debra.; Werner, Lise.; Moodley, Ramona.; Hong, Heather.; Kharsany, Ayesha Bibi Mahomed.; Mlisana, Koleka Patience.; Sibeko, Sengeziwe.; Garrett, Nigel Joel.; Chopera, Denis Rutendo.; Carr, William Henry.; Abdool Karim, Quarraisha.; Hill, Adrian V. S.; Abdool Karim, Salim Safurdeen.; Altfeld, Marcus.; Gray, Clive M.; Ndung'u, Peter Thumbi.
Abstract available in PDF file.
Nef-mediated down-regulation of CD4 and HLA class I in HIV-1 subtype C infection: association with disease progression and influence of immune pressure.
(Elsevier., 2014) Mann, Jaclyn Kelly.; Chopera, Denis Rutendo.; Omarjee, Saleha.; Kuang, Xiaomei T.; Le, Anh Q.; Anmole, Gursev.; Danroth, Ryan.; Mwimanzi, Philip.; Reddy, Tarylee.; Carlson, Jonathan M.; Radebe, Mopo.; Goulder, Philip Jeremy Renshaw.; Walker, Bruce D.; Abdool Karim, Salim Safurdeen.; Novitsky, Vladimir.; Williamson, Carolyn.; Brockman, Mark A.; Brumme, Zabrina L.; Ndung'u, Peter Thumbi.
Abstract available in pdf.
No evidence for selection of HIV-1 with enhanced gag-protease or nef function among breakthrough infections in the CAPRISA 004 tenofovir microbicide trial.
(2013) Chopera, Denis Rutendo.; Mann, Jaclyn Kelly.; Mwimanzi, Philip.; Omarjee, Saleha.; Kuang, Xiaomei T.; Ndabambi, Nonkululeko.; Goodier, Sarah A.; Martin, Eric.; Naranbhai, Vivek.; Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Brumme, Zabrina L.; Ndung'u, Peter Thumbi.; Williamson, Carolyn.; Brockman, Mark A.
Background: Use of antiretroviral-based microbicides for HIV-1 prophylaxis could introduce a transmission barrier that inadvertently facilitates the selection of fitter viral variants among incident infections. To investigate this, we assessed the in vitro function of gag-protease and nef sequences from participants who acquired HIV-1 during the CAPRISA 004 1% tenofovir microbicide gel trial. Methods and Results: We isolated the earliest available gag-protease and nef gene sequences from 83 individuals and examined their in vitro function using recombinant viral replication capacity assays and surface protein down regulation assays, respectively. No major phylogenetic clustering and no significant differences in gag-protease or nef function were observed in participants who received tenofovir gel versus placebo gel prophylaxis. Conclusion: Results indicate that the partial protective effects of 1% tenofovir gel use in the CAPRISA 004 trial were not offset by selection of transmitted/early HIV-1 variants with enhanced Gag-Protease or Nef fitness.
Temporal association of HLA-B*81:01- and HLA-B*39:10-mediated HIV-1 p24 sequence evolution with disease progression.
(American Society for Microbiology., 2012) Ntale, Roman.; Chopera, Denis Rutendo.; Ngandu, Nobubelo K.; de Assis Rosa, Debra.; Zembe, Lycias.; Gamieldien, Hoyam.; Mlotshwa, Mandla.; Werner, Lise.; Woodman, Zenda.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Gray, Clive M.; Williamson, Carolyn.
HLA-B*81:01 and HLA-B*39:10 alleles have been associated with viremic control in HIV-1 subtype C infection. Both alleles restrict the TL9 epitope in p24 Gag, and cytotoxic-T-lymphocyte (CTL)-mediated escape mutations in this epitope have been associated with an in vitro fitness cost to the virus. We investigated the timing and impact of mutations in the TL9 epitope on disease progression in five B*81:01- and two B*39:10-positive subtype C-infected individuals. Whereas both B*39:10 participants sampled at 2 months postinfection had viruses with mutations in the TL9 epitope, in three of the five (3/5) B*81:01 participants, TL9 escape mutations were only detected 10 months after infection, taking an additional 10 to 15 months to reach fixation. In the two remaining B*81:01 individuals, one carried a TL9 escape variant at 2 weeks postinfection, whereas no escape mutations were detected in the virus from the other participant for up to 33 months postinfection, despite CTL targeting of the epitope. In all participants, escape mutations in TL9 were linked to coevolving residues in the region of Gag known to be associated with host tropism. Late escape in TL9, together with coevolution of putative compensatory mutations, coincided with a spontaneous increase in viral loads in two individuals who were otherwise controlling the infection. These results provide in vivo evidence of the detrimental impact of B*81:01-mediated viral evolution, in a single Gag p24 epitope, on the control of viremia.
Transmission of HIV-1 CTL escape variants provides HLA - mismatched recipients with a survival advantage.
(Plos., 2007) Chopera, Denis Rutendo.; Woodman, Zenda.; Mlisana, Koleka Patience.; Mlotshwa, Mandla.; Martin, Darren Patrick.; Seoighe, Cathal.; Treurnicht, Florette K.; de Assis Rosa, Debra.; Hide, Winston.; Abdool Karim, Salim Safurdeen.; Gray, Clive M.; Williamson, Carolyn.
One of the most important genetic factors known to affect the rate of disease progression in HIV-infected individuals is the genotype at the Class I Human Leukocyte Antigen (HLA) locus, which determines the HIV peptides targeted by cytotoxic T-lymphocytes (CTLs). Individuals with HLA-B*57 or B*5801 alleles, for example, target functionally important parts of the Gag protein. Mutants that escape these CTL responses may have lower fitness than the wild-type and can be associated with slower disease progression. Transmission of the escape variant to individuals without these HLA alleles is associated with rapid reversion to wild-type. However, the question of whether infection with an escape mutant offers an advantage to newly infected hosts has not been addressed. Here we investigate the relationship between the genotypes of transmitted viruses and prognostic markers of disease progression and show that infection with HLA-B*57/B*5801 escape mutants is associated with lower viral load and higher CD4+ counts.
Virological and Immunological Factors Associated with HIV-1 Differential Disease Progression in HLA-B*58:01-Positive Individuals.
(American Society for Microbiology., 2010) Chopera, Denis Rutendo.; Mlotshwa, Mandla.; Woodman, Zenda.; Mlisana, Koleka Patience.; de Assis Rosa, Debra.; Martin, Darren Patrick.; Abdool Karim, Salim Safurdeen.; Gray, Clive M.; Williamson, Carolyn.
Molecular epidemiology studies have identified HLA-B*58:01 as a protective HIV allele. However, not all B*58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B*58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24Gag and Nef, respectively. Failure to target the TW10 epitope in one B*58:01-positive individual was associated with low CD4 counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year post infection, B*58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n=5) retained significantly higher CD4 counts (P=0.04), but not lower viral loads, than non-B*58:01-positive individuals (n=17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B*58:01 allele.