Zaza Ndhlovu - Academia.edu (original) (raw)
Papers by Zaza Ndhlovu
The Journal of Immunology
Several studies suggest that CTL proliferation is one of the functions specifically associated wi... more Several studies suggest that CTL proliferation is one of the functions specifically associated with elite control of HIV, but IFN-γ is generally used to define HIV epitope-specific CTL immunodominance. We performed multi-dimensional intra-donor analysis of HIV CTL-specific cytokine production and proliferation against panels of HLA-matched optimal epitopes. 9 elite controllers (EC) and 8 subjects with progressive infection (CP) were studied. Our analysis revealed two main immunodominance patterns defined by either predominant IFN-γ production or proliferative capacity with very different hierarchies of responses. In the EC, 40% of epitope-specific CTL that produced IFN-γ after 6 h stimulation did not proliferate whereas 47% of CTL with strong proliferative capacity did not produce IFN-γ after 6h stimulation. The contrasting patterns of immunodominance were associated with different phenotypes of memory and exhaustion markers. HIV CP usually had little HIV-specific proliferative capa...
The Journal of Immunology
HLA class I alleles B27 and B57 are associated with protection against HIV-1 disease progression.... more HLA class I alleles B27 and B57 are associated with protection against HIV-1 disease progression. However, the majority of persons expressing these alleles experience progressive infection, and factors modulating the HLA protective effect remain unclear. Here, we performed a detailed analysis of HIV-1-specific CD8 T cell responses in both progressors and controllers expressing HLA B27 or B57 in terms of TCR recruitment, polyfunctionality, proliferation, avidity, differentiation phenotypes, and functional ability to inhibit viral replication. The data show that HLA B27- or B57-restricted CD8 T cells targeting the same epitopes could be clearly differentiated between controllers and progressors based on potency and cross-reactivity of recognition of HIV-1 and viral variants. This in turn was associated with distinct TCR usage. Superior control of replication of HIV-1 and viral variants was observed by cross-reactive TCR-equipped CD8 T cells while highly antiviral efficacy was associat...
Frontiers in Virology
HIV variants present in the reservoir, particularly in tissues, may differ from those present in ... more HIV variants present in the reservoir, particularly in tissues, may differ from those present in peripheral blood prior to therapy initiation, and characterisation of these reservoir variants could better inform immune-based interventions for HIV cure. In the present study, Gag sequence differences between variants derived from the lymph node and peripheral blood mononuclear cell (PBMC) reservoirs as well as those derived from pre-therapy plasma, were investigated in 24 HIV-1 subtype C-infected individuals. HIVgagamplification was successful for 20 individuals, where 4 were controls including one untreated individual and 3 early treated individuals with LN collection within 2 weeks of treatment initiation. The remaining 16 individuals with LN and PBMC collection > 3 months after treatment initiation (median = 665 days), were further characterised. Recombinant viruses encoding patient-derived Gag-protease sequences from the pre-therapy plasma, LN reservoir, and PBMC reservoir, wer...
Nature
The extent to which Omicron infection1–9, with or without previous vaccination, elicits protectio... more The extent to which Omicron infection1–9, with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. Here we measured the neutralization capacity against variants of severe acute respiratory syndrome coronavirus 2 in 39 individuals in South Africa infected with the Omicron sublineage BA.1 starting at a median of 6 (interquartile range 3–9) days post symptom onset and continuing until last follow-up sample available, a median of 23 (interquartile range 19–27) days post symptoms to allow BA.1-elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer's BNT162b2 or Johnson & Johnson's Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean 50% focus reduction neutralization test titre of 42 at enrolment to 575 at the last follow-up time point (13.6-fold) in vaccinated participants and from 46 to 272 (6....
Science Translational Medicine, 2022
SARS-CoV-2 variants that escape neutralization and potentially affect vaccine efficacy have emerg... more SARS-CoV-2 variants that escape neutralization and potentially affect vaccine efficacy have emerged. T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is incompletely understood. We assessed neutralizing antibody and T cell responses in 44 South African COVID-19 patients either infected with the Beta variant (dominant from November 2020 to May 2021) or infected before its emergence (first wave, Wuhan strain) to provide an overall measure of immune evasion. We show that robust spike-specific CD4 and CD8 T cell responses were detectable in Beta-infected patients, similar to first-wave patients. Using peptides spanning the Beta-mutated regions, we identified CD4 T cell responses targeting the wild-type peptides in 12 of 22 first-wave patients, all of whom failed to recognize corresponding Beta-mutated peptides. However, responses to mutated regions formed only a small proportion (15.7%) of the...
Nature, 2021
The emergence of the SARS-CoV-2 variant of concern Omicron (Pango lineage B.1.1.529), first ident... more The emergence of the SARS-CoV-2 variant of concern Omicron (Pango lineage B.1.1.529), first identified in Botswana and South Africa, may compromise vaccine effectiveness and lead to re-infections1. Here we investigated Omicron escape from neutralization by antibodies from South African individuals vaccinated with Pfizer BNT162b2. We used blood samples taken soon after vaccination from individuals who were vaccinated and previously infected with SARS-CoV-2 or vaccinated with no evidence of previous infection. We isolated and sequence-confirmed live Omicron virus from an infected person and observed that Omicron requires the angiotensin-converting enzyme 2 (ACE2) receptor to infect cells. We compared plasma neutralization of Omicron relative to an ancestral SARS-CoV-2 strain and found that neutralization of ancestral virus was much higher in infected and vaccinated individuals compared with the vaccinated-only participants. However, both groups showed a 22-fold reduction in vaccine-elicited neutralization by the Omicron variant. Participants who were vaccinated and had previously been infected exhibited residual neutralization of Omicron similar to the level of neutralization of the ancestral virus observed in the vaccination-only group. These data support the notion that reasonable protection against Omicron may be maintained using vaccination approaches.
eLife, 2021
There are conflicting reports on the effects of HIV on COVID-19. Here, we analyzed disease severi... more There are conflicting reports on the effects of HIV on COVID-19. Here, we analyzed disease severity and immune cell changes during and after SARS-CoV-2 infection in 236 participants from South Africa, of which 39% were people living with HIV (PLWH), during the first and second (Beta dominated) infection waves. The second wave had more PLWH requiring supplemental oxygen relative to HIV-negative participants. Higher disease severity was associated with low CD4 T cell counts and higher neutrophil to lymphocyte ratios (NLR). Yet, CD4 counts recovered and NLR stabilized after SARS-CoV-2 clearance in wave 2 infected PLWH, arguing for an interaction between SARS-CoV-2 and HIV infection leading to low CD4 and high NLR. The first infection wave, where severity in HIV negative and PLWH was similar, still showed some HIV modulation of SARS-CoV-2 immune responses. Therefore, HIV infection can synergize with the SARS-CoV-2 variant to change COVID-19 outcomes.
Clinical Infectious Diseases, 2021
Background There is limited understanding of severe acute respiratory syndrome coronavirus 2 (SAR... more Background There is limited understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis in African populations with a high burden of infectious disease comorbidities such as human immunodeficiency virus (HIV). The kinetics, magnitude, and duration of virus-specific antibodies and B-cell responses in people living with HIV (PLWH) in sub-Saharan Africa have not been fully characterized. Methods We longitudinally followed SARS-CoV-2–infected individuals in Durban, KwaZulu-Natal, South Africa, and characterized SARS-CoV-2 receptor-binding domain-specific immunoglobulin (Ig) M, IgG, and IgA weekly for 1 month and at 3 months post-diagnosis. Thirty of 72 (41.7%) were PLWH, 25/30 (83%) of whom were on antiretroviral therapy (ART) with full HIV suppression. Plasma neutralization was determined using a live virus neutralization assay, and antibody-secreting cell population frequencies were determined by flow cytometry. Results Similar seroconversion rates, time...
Immunity, 2016
Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytoki... more Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-1 on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-1 infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-1 infection, lymphoid tissue breakdown, and persistent ...
AIDS Research and Human Retroviruses, 2014
Background: The use of progestin-only injectable contraception (IC) has been epidemiologically as... more Background: The use of progestin-only injectable contraception (IC) has been epidemiologically associated with increased risk of HIV acquisition but it remains unclear whether this relationship is causal and if so the mechanisms by which progestin-only contraceptives increase risk. Methods: Demographic and behavioral data along with blood and female genital tract (FGT) samples were obtained from a cohort of 18-23 year old HIV uninfected women in Durban South Africa. Cervical cytobrush cells were analyzed by flow cytometry and plasma progesterone measured by chemiluminescence. Cytokines in cervico-vaginal lavage (CVL) were measured by luminex. Results: Women using IC disproportionately accounted for new HIV infections during the study (RR 2.55 [1.90-3.42] p=0.0018). While 31.5% of women in the cohort used IC 72.7% of women who became HIV positive used IC (8 of 11); 9.09% of infected women did not use contraception. This difference was not accounted for by behavioral or demographic differences. The use of IC was significantly associated with a higher frequency of CD4+CCR5+ T cells of CD45+ cells in the cervix relative to those not on hormonal contraception (1.18% [0.33 4.53] vs. 0.29% [0.13 0.48] respectively; p=0.036). Women with high endogenous progesterone (>0.3ng/mL luteal phase) in the absence of IC use had significantly increased frequency of CD4+CCR5+ T cells in the cervix relative to those with low progesterone (follicular phase; 1.16% [0.51 3.76] of CD45+ cells vs 0.29% [0.13 0.48] respectively; p=0.042). High endogenous progesterone was also associated with a higher frequency of cervical CD4+CCR5+HLADR+CD38+ T cells (p=0.034). There was no observed difference based on IC use in soluble cytokine or chemokine levels in CVL. Conclusions: The increased frequency of HIV target cells at the site of exposure in the context of IC and high endogenous progesterone provides a potential biological mechanism for the increased HIV acquisition risk for women using injectable progestin-only contraceptives.
AIDS Research and Human Retroviruses, 2014
Proceedings of the National Academy of Sciences, 2010
The functional capacities of CD8+T cells important for virus clearance are influenced by interact... more The functional capacities of CD8+T cells important for virus clearance are influenced by interactions with antigen presenting cells (APCs) and CD4+T cells during initial selection, subsequent expansion, and development of memory. Recently, investigators have shown that polyfunctional T cells correlate best with long-term protection, however, it is still unknown how to stimulate T cells to achieve these responses. To study this, we examined the phenotypes and functions of CD8+T cells specific for two different virus antigens stimulated ex vivo using either autologous monocyte-derived dendritic cells (moDCs) or HLA-A2-Ig-based artificial APCs (aAPCs). Although similar numbers of influenza virus and measles virus tetramer-positive cells were generated by stimulation with peptide-loaded moDCs and aAPCs, T cell function, assessed by expression of IL-2, IFN-γ, TNF-α, MIP1β, and CD107a, showed that aAPC-generated CD8+T cells were multifunctional, whereas moDC-generated cells were mostly mo...
Nature Immunology, 2012
Human leukocyte antigen (HLA) B*27 and B*57 are associated with protection against HIV-1 disease ... more Human leukocyte antigen (HLA) B*27 and B*57 are associated with protection against HIV-1 disease progression, yet most persons expressing these alleles are unable to control HIV-1. Here we show that HLA-B*27-restricted CD8 + T cells in controllers and progressors differ in their ability to inhibit virus replication through targeting of the immunodominant Gag epitope. This is associated with distinct TCR clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity against epitope variants, and enhanced perforin delivery. Clonotypespecific differences in antiviral efficacy were also observed for an immunodominant HLA-B*57 restricted response in controllers and progressors. Thus, the efficacy of protective alleles is modulated by specific TCR clonotypes selected in natural infection, providing a functional explanation for divergent HIV-1 outcomes. A subset of HIV-1-infected persons, here termed elite controllers, are distinguished by their ability to maintain a state of apparent durable control of HIV-1 replication without the need for antiviral therapy 1,2. Viral control is linked to expression of certain human leukocyte antigen (HLA) class I alleles 3-5 , particularly B*57, B*27, and B*5801, suggesting an immunologic basis related to CD8 + T cell function. Indeed, a recent genome-wide
Journal of Virology, 2012
Analyses of the breadth and specificity of virus-specific CD8 + T cell responses associated with ... more Analyses of the breadth and specificity of virus-specific CD8 + T cell responses associated with control of HIV have largely relied on measurement of cytokine secretion by effector T cells. These have resulted in the identification of HIV elite controllers with low or absent responses in which non-T-cell mechanisms of control have been suggested. However, successful control of HIV infection may be associated with central memory T cells, which have not been consistently examined in these individuals. Gag-specific T cells were characterized using a peptide-based cultured enzyme-linked immunosorbent spot assay (ELISpot). Peripheral blood mononuclear cells from HIV elite controllers ( n = 10), progressors ( n = 12), and antiretroviral-treated individuals ( n = 9) were cultured with overlapping peptides for 12 days. Specificity was assessed by tetramer staining, functional features of expanded cells were assessed by cytokine secretion, and virus inhibition and phenotypic characteristics ...
The Journal of Immunology
Several studies suggest that CTL proliferation is one of the functions specifically associated wi... more Several studies suggest that CTL proliferation is one of the functions specifically associated with elite control of HIV, but IFN-γ is generally used to define HIV epitope-specific CTL immunodominance. We performed multi-dimensional intra-donor analysis of HIV CTL-specific cytokine production and proliferation against panels of HLA-matched optimal epitopes. 9 elite controllers (EC) and 8 subjects with progressive infection (CP) were studied. Our analysis revealed two main immunodominance patterns defined by either predominant IFN-γ production or proliferative capacity with very different hierarchies of responses. In the EC, 40% of epitope-specific CTL that produced IFN-γ after 6 h stimulation did not proliferate whereas 47% of CTL with strong proliferative capacity did not produce IFN-γ after 6h stimulation. The contrasting patterns of immunodominance were associated with different phenotypes of memory and exhaustion markers. HIV CP usually had little HIV-specific proliferative capa...
The Journal of Immunology
HLA class I alleles B27 and B57 are associated with protection against HIV-1 disease progression.... more HLA class I alleles B27 and B57 are associated with protection against HIV-1 disease progression. However, the majority of persons expressing these alleles experience progressive infection, and factors modulating the HLA protective effect remain unclear. Here, we performed a detailed analysis of HIV-1-specific CD8 T cell responses in both progressors and controllers expressing HLA B27 or B57 in terms of TCR recruitment, polyfunctionality, proliferation, avidity, differentiation phenotypes, and functional ability to inhibit viral replication. The data show that HLA B27- or B57-restricted CD8 T cells targeting the same epitopes could be clearly differentiated between controllers and progressors based on potency and cross-reactivity of recognition of HIV-1 and viral variants. This in turn was associated with distinct TCR usage. Superior control of replication of HIV-1 and viral variants was observed by cross-reactive TCR-equipped CD8 T cells while highly antiviral efficacy was associat...
Frontiers in Virology
HIV variants present in the reservoir, particularly in tissues, may differ from those present in ... more HIV variants present in the reservoir, particularly in tissues, may differ from those present in peripheral blood prior to therapy initiation, and characterisation of these reservoir variants could better inform immune-based interventions for HIV cure. In the present study, Gag sequence differences between variants derived from the lymph node and peripheral blood mononuclear cell (PBMC) reservoirs as well as those derived from pre-therapy plasma, were investigated in 24 HIV-1 subtype C-infected individuals. HIVgagamplification was successful for 20 individuals, where 4 were controls including one untreated individual and 3 early treated individuals with LN collection within 2 weeks of treatment initiation. The remaining 16 individuals with LN and PBMC collection > 3 months after treatment initiation (median = 665 days), were further characterised. Recombinant viruses encoding patient-derived Gag-protease sequences from the pre-therapy plasma, LN reservoir, and PBMC reservoir, wer...
Nature
The extent to which Omicron infection1–9, with or without previous vaccination, elicits protectio... more The extent to which Omicron infection1–9, with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. Here we measured the neutralization capacity against variants of severe acute respiratory syndrome coronavirus 2 in 39 individuals in South Africa infected with the Omicron sublineage BA.1 starting at a median of 6 (interquartile range 3–9) days post symptom onset and continuing until last follow-up sample available, a median of 23 (interquartile range 19–27) days post symptoms to allow BA.1-elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer's BNT162b2 or Johnson & Johnson's Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean 50% focus reduction neutralization test titre of 42 at enrolment to 575 at the last follow-up time point (13.6-fold) in vaccinated participants and from 46 to 272 (6....
Science Translational Medicine, 2022
SARS-CoV-2 variants that escape neutralization and potentially affect vaccine efficacy have emerg... more SARS-CoV-2 variants that escape neutralization and potentially affect vaccine efficacy have emerged. T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is incompletely understood. We assessed neutralizing antibody and T cell responses in 44 South African COVID-19 patients either infected with the Beta variant (dominant from November 2020 to May 2021) or infected before its emergence (first wave, Wuhan strain) to provide an overall measure of immune evasion. We show that robust spike-specific CD4 and CD8 T cell responses were detectable in Beta-infected patients, similar to first-wave patients. Using peptides spanning the Beta-mutated regions, we identified CD4 T cell responses targeting the wild-type peptides in 12 of 22 first-wave patients, all of whom failed to recognize corresponding Beta-mutated peptides. However, responses to mutated regions formed only a small proportion (15.7%) of the...
Nature, 2021
The emergence of the SARS-CoV-2 variant of concern Omicron (Pango lineage B.1.1.529), first ident... more The emergence of the SARS-CoV-2 variant of concern Omicron (Pango lineage B.1.1.529), first identified in Botswana and South Africa, may compromise vaccine effectiveness and lead to re-infections1. Here we investigated Omicron escape from neutralization by antibodies from South African individuals vaccinated with Pfizer BNT162b2. We used blood samples taken soon after vaccination from individuals who were vaccinated and previously infected with SARS-CoV-2 or vaccinated with no evidence of previous infection. We isolated and sequence-confirmed live Omicron virus from an infected person and observed that Omicron requires the angiotensin-converting enzyme 2 (ACE2) receptor to infect cells. We compared plasma neutralization of Omicron relative to an ancestral SARS-CoV-2 strain and found that neutralization of ancestral virus was much higher in infected and vaccinated individuals compared with the vaccinated-only participants. However, both groups showed a 22-fold reduction in vaccine-elicited neutralization by the Omicron variant. Participants who were vaccinated and had previously been infected exhibited residual neutralization of Omicron similar to the level of neutralization of the ancestral virus observed in the vaccination-only group. These data support the notion that reasonable protection against Omicron may be maintained using vaccination approaches.
eLife, 2021
There are conflicting reports on the effects of HIV on COVID-19. Here, we analyzed disease severi... more There are conflicting reports on the effects of HIV on COVID-19. Here, we analyzed disease severity and immune cell changes during and after SARS-CoV-2 infection in 236 participants from South Africa, of which 39% were people living with HIV (PLWH), during the first and second (Beta dominated) infection waves. The second wave had more PLWH requiring supplemental oxygen relative to HIV-negative participants. Higher disease severity was associated with low CD4 T cell counts and higher neutrophil to lymphocyte ratios (NLR). Yet, CD4 counts recovered and NLR stabilized after SARS-CoV-2 clearance in wave 2 infected PLWH, arguing for an interaction between SARS-CoV-2 and HIV infection leading to low CD4 and high NLR. The first infection wave, where severity in HIV negative and PLWH was similar, still showed some HIV modulation of SARS-CoV-2 immune responses. Therefore, HIV infection can synergize with the SARS-CoV-2 variant to change COVID-19 outcomes.
Clinical Infectious Diseases, 2021
Background There is limited understanding of severe acute respiratory syndrome coronavirus 2 (SAR... more Background There is limited understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis in African populations with a high burden of infectious disease comorbidities such as human immunodeficiency virus (HIV). The kinetics, magnitude, and duration of virus-specific antibodies and B-cell responses in people living with HIV (PLWH) in sub-Saharan Africa have not been fully characterized. Methods We longitudinally followed SARS-CoV-2–infected individuals in Durban, KwaZulu-Natal, South Africa, and characterized SARS-CoV-2 receptor-binding domain-specific immunoglobulin (Ig) M, IgG, and IgA weekly for 1 month and at 3 months post-diagnosis. Thirty of 72 (41.7%) were PLWH, 25/30 (83%) of whom were on antiretroviral therapy (ART) with full HIV suppression. Plasma neutralization was determined using a live virus neutralization assay, and antibody-secreting cell population frequencies were determined by flow cytometry. Results Similar seroconversion rates, time...
Immunity, 2016
Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytoki... more Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-1 on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-1 infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-1 infection, lymphoid tissue breakdown, and persistent ...
AIDS Research and Human Retroviruses, 2014
Background: The use of progestin-only injectable contraception (IC) has been epidemiologically as... more Background: The use of progestin-only injectable contraception (IC) has been epidemiologically associated with increased risk of HIV acquisition but it remains unclear whether this relationship is causal and if so the mechanisms by which progestin-only contraceptives increase risk. Methods: Demographic and behavioral data along with blood and female genital tract (FGT) samples were obtained from a cohort of 18-23 year old HIV uninfected women in Durban South Africa. Cervical cytobrush cells were analyzed by flow cytometry and plasma progesterone measured by chemiluminescence. Cytokines in cervico-vaginal lavage (CVL) were measured by luminex. Results: Women using IC disproportionately accounted for new HIV infections during the study (RR 2.55 [1.90-3.42] p=0.0018). While 31.5% of women in the cohort used IC 72.7% of women who became HIV positive used IC (8 of 11); 9.09% of infected women did not use contraception. This difference was not accounted for by behavioral or demographic differences. The use of IC was significantly associated with a higher frequency of CD4+CCR5+ T cells of CD45+ cells in the cervix relative to those not on hormonal contraception (1.18% [0.33 4.53] vs. 0.29% [0.13 0.48] respectively; p=0.036). Women with high endogenous progesterone (>0.3ng/mL luteal phase) in the absence of IC use had significantly increased frequency of CD4+CCR5+ T cells in the cervix relative to those with low progesterone (follicular phase; 1.16% [0.51 3.76] of CD45+ cells vs 0.29% [0.13 0.48] respectively; p=0.042). High endogenous progesterone was also associated with a higher frequency of cervical CD4+CCR5+HLADR+CD38+ T cells (p=0.034). There was no observed difference based on IC use in soluble cytokine or chemokine levels in CVL. Conclusions: The increased frequency of HIV target cells at the site of exposure in the context of IC and high endogenous progesterone provides a potential biological mechanism for the increased HIV acquisition risk for women using injectable progestin-only contraceptives.
AIDS Research and Human Retroviruses, 2014
Proceedings of the National Academy of Sciences, 2010
The functional capacities of CD8+T cells important for virus clearance are influenced by interact... more The functional capacities of CD8+T cells important for virus clearance are influenced by interactions with antigen presenting cells (APCs) and CD4+T cells during initial selection, subsequent expansion, and development of memory. Recently, investigators have shown that polyfunctional T cells correlate best with long-term protection, however, it is still unknown how to stimulate T cells to achieve these responses. To study this, we examined the phenotypes and functions of CD8+T cells specific for two different virus antigens stimulated ex vivo using either autologous monocyte-derived dendritic cells (moDCs) or HLA-A2-Ig-based artificial APCs (aAPCs). Although similar numbers of influenza virus and measles virus tetramer-positive cells were generated by stimulation with peptide-loaded moDCs and aAPCs, T cell function, assessed by expression of IL-2, IFN-γ, TNF-α, MIP1β, and CD107a, showed that aAPC-generated CD8+T cells were multifunctional, whereas moDC-generated cells were mostly mo...
Nature Immunology, 2012
Human leukocyte antigen (HLA) B*27 and B*57 are associated with protection against HIV-1 disease ... more Human leukocyte antigen (HLA) B*27 and B*57 are associated with protection against HIV-1 disease progression, yet most persons expressing these alleles are unable to control HIV-1. Here we show that HLA-B*27-restricted CD8 + T cells in controllers and progressors differ in their ability to inhibit virus replication through targeting of the immunodominant Gag epitope. This is associated with distinct TCR clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity against epitope variants, and enhanced perforin delivery. Clonotypespecific differences in antiviral efficacy were also observed for an immunodominant HLA-B*57 restricted response in controllers and progressors. Thus, the efficacy of protective alleles is modulated by specific TCR clonotypes selected in natural infection, providing a functional explanation for divergent HIV-1 outcomes. A subset of HIV-1-infected persons, here termed elite controllers, are distinguished by their ability to maintain a state of apparent durable control of HIV-1 replication without the need for antiviral therapy 1,2. Viral control is linked to expression of certain human leukocyte antigen (HLA) class I alleles 3-5 , particularly B*57, B*27, and B*5801, suggesting an immunologic basis related to CD8 + T cell function. Indeed, a recent genome-wide
Journal of Virology, 2012
Analyses of the breadth and specificity of virus-specific CD8 + T cell responses associated with ... more Analyses of the breadth and specificity of virus-specific CD8 + T cell responses associated with control of HIV have largely relied on measurement of cytokine secretion by effector T cells. These have resulted in the identification of HIV elite controllers with low or absent responses in which non-T-cell mechanisms of control have been suggested. However, successful control of HIV infection may be associated with central memory T cells, which have not been consistently examined in these individuals. Gag-specific T cells were characterized using a peptide-based cultured enzyme-linked immunosorbent spot assay (ELISpot). Peripheral blood mononuclear cells from HIV elite controllers ( n = 10), progressors ( n = 12), and antiretroviral-treated individuals ( n = 9) were cultured with overlapping peptides for 12 days. Specificity was assessed by tetramer staining, functional features of expanded cells were assessed by cytokine secretion, and virus inhibition and phenotypic characteristics ...