Project Title

Characterisation of Viral Reservoirs among HIV-1 non-B Vertically Infected Adolescents receiving Antiretroviral Therapy in Cameroon

EDCTP Project Call

Career Development Fellowship (CDF)

Project Objectives

1- Determine HIV-1 genetic variability and drug resistance in cellular reservoirs; 2- Characterize immune activation/inflammation; 3- Evaluate the size of HIV reservoir; 4- Evaluate the effect of antiretroviral therapy and immune response on the viral reservoir profile

Study Design

Observational and comparative study

Project Summary

Antiretroviral therapy (ART) can bring HIV-1 in blood plasma to an undetectable level. Unfortunately, ART is not curative, as within a few weeks of ART cessation, HIV viremia rebounds in most patients. The primary source of this rebound is the highly stable reservoir of latent yet replication-competent HIV-1 proviruses integrated into the genomic DNA of resting memory CD4+ T cells. To achieve a cure for HIV, understanding the cell reservoir environment is of paramount importance. Mechanisms of reservoir maintenance generally depend on levels/type of immune recognition and dynamics of viral persistence; they are differ between adults and adolescents, a stage during which suboptimal adherence is more frequent. The main objective of this study was to characterize HIV reservoirs in vertically infected adolescents; specifically, we wanted to determine HIV-1 genetic variability and drug resistance in cellular reservoirs, evaluate immune status and quantify HIV reservoirs in these adolescents. To achieve these objectives, we recruited assenting adolescents (in addition to parental consent) infected with HIV-1 in the Centre Region of Cameroon. We also recruited HIV- assenting children (in addition to parental consent) as control group for immune status evaluation. We collected 10 mL of intravenous blood to conduct the following tests: CD4/CD8 count, plasmatic viral load, peripheral mononuclear cells (PBMCs) isolation, immune profile markers, genotyping and viral reservoir quantification. During this reporting period, we recruited 87 HIV+ Participants in addition to 60 participants from 1st year for a total of 147 HIV+ participants and 30 HIV- participants. Overall, HIV+ participants consisted of 46.2% males with a sex ratio of 0.9. The mean age was 15,44 years old. HIV- participants consisted of 56.7% males with a sex ratio of 1.3. The mean age was 14.6 years old. The majority (70.1%) of HIV+ were on Tenofovir + Lamivudine + Dolutegravir (TLD) ART regimen. The median duration under the current ART was 22 months. The median plasmatic HIV-1 viral load was 1,411 copies/mL, with the majority (85%) of participants having viral load < 1,000 copies/mL (virological success). The median CD4 cell count was 823 cells/mm3; 76.9% of the adolescents had CD4 cells greater than 500 cells/mm3 (immunocompetent), and 2.8% of adolescents were immunocompromised with CD4 counts less than 200 cells/mm3. Eighty-seven percent of our participants harbored at least one major archived drug resistance mutation in their reservoirs, the most prevalent being the K103N mutation (52%), a non-nucleotide reverse transcriptase inhibitor (NNRTI) associated mutation causing high level resistance to nevirapine (NVP) and efavirenz (EFZ). M184V was the second most prevalent HIV drug resistance mutation found (32%), a nucleotide reverse transcriptase inhibitor-associated mutation causing high level resistance to lamivudine (3TC) and emtracitabine (FTC). All participants were infected with non-B HIV-1 subtypes. Most of our participants (69%) were infected with HIV-1 CRF02_AG, therefore confirming the broad diversity and the predominance of HIV-1 CRF02_AG in Cameroon. The assessment of the immune profile resulted in the identification of CD4 and CD8 T cell subsets. HIV vertically infected adolescents showed an increased median number of effector, central memory and effector memory CD4 T cells. In contrast, HIV negative participants displayed a significant increase in naïve CD4 T cells. The same trend was observed for CD8 T cells. In HIV+ adolescents, immune activation was significantly high in naïve, effector, central memory and effector memory CD4 T cells; The same trend was observed for CD8 T cells. We obtained a median HIV-DNA concentration of 4.00 log10 copies/106 CD4+T cells. Total HIV-DNA was lower in participants who had a longer time on ART with median values of 3.23 versus 2.9 log10 copies/106 CD4+T cells than in participants who that initiated ART later. A small difference was observed between adolescents whose mothers followed antiretroviral treatment for the prevention of mother to child transmission of HIV and those who did not. Total HIV-DNA was correlated with plasmatic HIV-RNA, CD4+T cells and CD4/CD8 ratio. Plasma HIV-RNA significantly increased in relation with higher HIV-DNA levels. Conversely, CD8+T cells significantly decreased in relation to higher HIV-DNA levels; accordingly, CD4/CD8 ratio significantly decreased in relation to higher HIV-DNA levels.

Host Organisation

Results & Outcomes

Current Organisation

Chantal Biya International Reference Centre (CIRCB)

Current Job Title

Researcher

Biography

Publications