Browsing by Author "Selhorst, Philippe"
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- ItemOpen AccessCase report: mechanisms of HIV elite control in two African women(BioMed Central, 2018-01-25) Moosa, Yumna; Tanko, Ramla F; Ramsuran, Veron; Singh, Ravesh; Madzivhandila, Mashudu; Yende-Zuma, Nonhlanhla; Abrahams, Melissa-Rose; Selhorst, Philippe; Gounder, Kamini; Moore, Penny L; Williamson, Carolyn; Abdool Karim, Salim S; Garrett, Nigel J; Burgers, Wendy ABackground: The majority of people living with HIV require antiretroviral therapy (ART) for controlling viral replication, however there are rare HIV controllers who spontaneously and durably control HIV in the absence of treatment. Understanding what mediates viral control in these individuals has provided us with insights into the immune mechanisms that may be important to induce for a vaccine or functional cure for HIV. To date, few African elite controllers from high incidence settings have been described. We identified virological controllers from the CAPRISA 002 cohort of HIV-1 subtype C infected women in KwaZulu Natal, South Africa, two (1%) of whom were elite controllers. We examined the genetic, clinical, immunological and virological characteristics of these two elite HIV controllers in detail, to determine whether they exhibit features of putative viral control similar to those described for elite controllers reported in the literature. Case presentation: In this case report, we present clinical features, CD4+ T cell and viral load trajectories for two African women over 7 years of HIV infection. Viral load became undetectable 10 months after HIV infection in Elite Controller 1 (EC1), and after 6 weeks in Elite Controller 2 (EC2), and remained undetectable for the duration of follow-up, in the absence of ART. Both elite controllers expressed multiple HLA Class I and II haplotypes previously associated with slower disease progression (HLA-A*74:01, HLA-B*44:03, HLA-B*81:01, HLA-B*57:03, HLA-DRB1*13). Fitness assays revealed that both women were infected with replication competent viruses, and both expressed higher mRNA levels of p21, a host restriction factor associated with viral control. HIV-specific T cell responses were examined using flow cytometry. EC1 mounted high frequency HIV-specific CD8+ T cell responses, including a B*81: 01-restricted Gag TL9 response. Unusually, EC2 had evidence of pre-infection HIV-specific CD4+ T cell responses. Conclusion: We identified some features typical of elite controllers, including high magnitude HIV-specific responses and beneficial HLA. In addition, we made the atypical finding of pre-infection HIV-specific immunity in one elite controller, that may have contributed to very early viral control. This report highlights the importance of studying HIV controllers in high incidence settings.
- ItemOpen AccessCharacterisation of HIV-1 Envelope features of breakthrough infections from the CAPRISA 004 Microbicide Trial(2016) Ismail, Sherazaan Dineo; Williamson, Carolyn; Selhorst, PhilippeThe CAPRISA 004 trial demonstrated the safety and a 39% efficacy of a 1% tenofovir (TFV) gel for the prevention of HIV-1 acquisition in young African women. It was subsequently shown that women assigned to the TFV arm who became infected had higher viral loads, slower anti-HIV-1 antibody avidity maturation, and higher Gag-specific IFN-γ+ CD4+ T cell responses; although replication capacity, as measured by Gag-Pro recombinant viruses, did not differ between arms. We thus aimed to investigate if there were differences in Envelope function, or TFV susceptibility, which may be selected for during transmission in those who became infected despite being assigned to the TFV arm. Viruses from 39 out of 48 recently HIV-1 infected individuals from the trial (matched on time post-infection and the presence of protective HLAs) were isolated. Isolate env genes were sequenced using a single genome amplification approach and were compared to plasma sequences from the same time-point. To evaluate phenotypic characteristics of env, inhibition assays were performed using the following inhibitors: tenofovir, maraviroc, T20, PSC-RANTES and anti-CD4 antibody clone SK3. In addition, envs for 19 participants were cloned and used to generate pseudoviruses which were evaluated for entry efficiency. Viral isolates were identical or very similar to viruses in circulation in vivo; however had a lower diversity, indicating that they were representative of in vivo virus but did not reflect the entire quasispecies in plasma. The TFV arm viruses were not more resistant to TFV than those in the placebo arm. A comparison of variable loop characteristics, distance to a consensus representative of viruses circulating in the region, and sensitivity to inhibitors or entry efficiencies of the viruses, also found no difference in genotypic nor phenotypic properties between study arms. When assessing the impact of viral phenotype on markers of disease progression, it was found that sensitivity to inhibitors did not contribute to VL or CD4+ count in this cohort. To evaluate envelope in isolation of the rest of the genome, pseudoviruses were generated from 11 participants. We found that PSV entry efficiency did not correlate with VL at isolation, 3 months post-infection and set-point, or with CD4+ counts at set-point. However, pseudovirus inhibitor sensitivities were significantly different to those of isolates for the inhibitors T20, anti-CD4 antibody SK3 and PSC-RANTES. Overall, the isolate env genotypic and phenotypic characteristics investigated in this study did not differ between trial arms. Interestingly, pseudoviruses showed significant differences in their sensitivity to entry inhibitors when compared to their corresponding isolate, highlighting the importance of caution when interpreting data from in vitro studies, and motivates for further evaluation of in vitro models.
- ItemOpen AccessDetectable HIV-1 in semen in individuals with very low blood viral loads(2020-03-05) Kariuki, Samuel M; Selhorst, Philippe; Norman, Jennifer; Cohen, Karen; Rebe, Kevin; Williamson, Carolyn; Dorfman, Jeffrey RAbstract Background Several reports indicate that a portion (5–10%) of men living with HIV-1 intermittently shed HIV-1 RNA into seminal plasma while on long term effective antiretroviral therapy (ART). This is highly suggestive of an HIV-1 reservoir in the male genital tract. However, the status of this reservoir in men living with HIV-1 who are not under treatment is underexplored and has implications for understanding the origins and evolution of the reservoir. Finding Forty-three HIV-1 positive, antiretroviral therapy naïve study participants attending a men’s health clinic were studied. Semen viral loads and blood viral loads were generally correlated, with semen viral loads generally detected in individuals with blood viral loads > 10,000 cp/ml. However, we found 1 individual with undetectable viral loads (<20cp/ml) and 2 individuals with very low blood viral load (97 and 333cp/ml), but with detectable HIV-1 in semen (485–1157 copies/semen sample). Blood viral loads in the first individual were undetectable when tested three times over the prior 5 years. Conclusions Semen HIV-1 viral loads are usually related to blood viral loads, as we confirm. Nonetheless, this was not true in a substantial minority of individuals suggesting unexpectedly high levels of replication in the male genital tract in a few individuals, despite otherwise effective immune control. This may reflect establishment of a local reservoir of HIV-1 populations.
- ItemOpen AccessThe HIV‑1 transmission bottleneck(Biomed Central, 2017-03-25) Kariuki, Samuel Mundia; Selhorst, Philippe; Ariën, Kevin K; Dorfman, Jeffrey RobertIt is well established that most new systemic infections of HIV-1 can be traced back to one or a limited number of founder viruses. Usually, these founders are more closely related to minor HIV-1 populations in the blood of the presumed donor than to more abundant lineages. This has led to the widely accepted idea that transmission selects for viral characteristics that facilitate crossing the mucosal barrier of the recipient’s genital tract, although the specific selective forces or advantages are not completely defined. However, there are other steps along the way to becoming a founder virus at which selection may occur. These steps include the transition from the donor’s general circulation to the genital tract compartment, survival within the transmission fluid, and establishment of a nascent stable local infection in the recipient’s genital tract. Finally, there is the possibility that important narrowing events may also occur during establishment of systemic infection. This is suggested by the surprising observation that the number of founder viruses detected after transmission in intravenous drug users is also limited. Although some of these steps may be heavily selective, others may result mostly in a stochastic narrowing of the available founder pool. Collectively, they shape the initial infection in each recipient.
- ItemOpen AccessThe HIV-1 transmission bottleneck(BioMed Central, 2017-03-23) Kariuki, Samuel M; Selhorst, Philippe; Ariën, Kevin K; Dorfman, Jeffrey RIt is well established that most new systemic infections of HIV-1 can be traced back to one or a limited number of founder viruses. Usually, these founders are more closely related to minor HIV-1 populations in the blood of the presumed donor than to more abundant lineages. This has led to the widely accepted idea that transmission selects for viral characteristics that facilitate crossing the mucosal barrier of the recipient’s genital tract, although the specific selective forces or advantages are not completely defined. However, there are other steps along the way to becoming a founder virus at which selection may occur. These steps include the transition from the donor’s general circulation to the genital tract compartment, survival within the transmission fluid, and establishment of a nascent stable local infection in the recipient’s genital tract. Finally, there is the possibility that important narrowing events may also occur during establishment of systemic infection. This is suggested by the surprising observation that the number of founder viruses detected after transmission in intravenous drug users is also limited. Although some of these steps may be heavily selective, others may result mostly in a stochastic narrowing of the available founder pool. Collectively, they shape the initial infection in each recipient.