Published on December 14, 2018 | Updated on April 15, 2019

ClonaRetro Project

Deciphering retroviral clonality in non-human primates naturally coinfected with different exogenous retroviruses

Co-leaders : Renaud Mahieux (CIRI) & David Fouchet (LBBE)

Humans can be infected by at least three different families of exogenous retroviruses: Human T-Lymphotropic Virus type 1 (HTLV-1), Human Immunodeficiency Virus type 1 (HIV-1) and Human Foamy Viruses (HFV). HTLV-1 infects 5-10 million people worldwide. This retrovirus causes a malignant lymphoproliferative disease called Adult T-cell Leukemia/Lymphoma (ATLL), and of HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HIV-1 infects more than 30 million individuals and causes AIDS. So far, HFV has been detected in more than 100 cases but this number is very likely to be underestimated since thousands of individuals are exposed each year to Non-Human Primate (NHPs) fluids through severe bites. HFV infection is asymptomatic. Importantly, cases of HIV-1/HTLV-1 or HTLV-1/HFV co-infection have been reported. In vivo, integrated HTLV-1, HIV-1 and HFV genomes (i.e. proviruses) are detected in CD4+ T-lymphocytes. In addition, in HTLV-1 infection a high proviral load (PVL), i.e. the percentage of circulating HTLV-1-infected lymphocytes, is strongly associated with a high risk of developing an HTLV-1-related disease.
In a retrovirus-infected host, the virus can propagate and increase the PVL by two routes: first, de novo infection of cells by virions which then undergo reverse transcription and integrate in a new genomic site; second, by clonal expansion of the already infected cells in the absence of viral replication. HTLV-1 replicates mostly via clonal expansion. Individual clones of infected cells containing replication-competent viruses can persist in patients for several years. This pseudolatency renders HTLV-1 resistant to antiretroviral drugs and contributes to viral escape from the host immune response. HFV varies little in sequence, suggesting that HFV is also able to drive clonal expansion of the infected cells, but direct evidence is lacking. In contrast, HIV-1 replicates almost exclusively via de novo infection, and viral expression promotes apoptosis.
Simian T-Lymphotropic Virus type 1 (STLV-1) is the simian counterpart of HTLV-1. HTLV-1 and STLV-1 are almost identical at the nucleotide sequence level and some NHPs develop STLV-1-associated diseases such as ATLL, while as in humans, most animals remain asymptomatic. Previous report showed that, in Mandrill and Baboon, STLV-1 is mostly transmitted through aggressive contacts rather than during sexual activity. Simian Immunodeficiency Virus type 1 (SIV-1) infection is also usually asymptomatic in naturally infected NHPs. At least 31 and 45 NHP species are infected with STLV-1 and SIV, respectively. As in humans, Simian Foamy Virus (SFV) infection is asymptomatic and SFV seroprevalence reaches >75% in captive and wild NHPs. Since the three retroviruses have common modes of transmission, co-infection is frequent in non-human primates.
In this project, we will quantify the impact of co-infection with exogenous retroviruses on viral clonality. We will study SFV and STLV-1 clonality in the case of natural infection with one (SFV), two (SFV/STLV-1, STLV-1/SIV) or three (SFV/STLV/SIV) viruses, in two closely related species (baboons, mandrills).
Clonality analysis represents a powerful tool to understand viral infections within host ecology and the potential ways through which parasites can interact. The results of this work will identify the factors that correlate with retroviral clonality and allow us to test specific hypotheses on the impact of retroviral co-infection on clonality. By comparing the dynamics of clonality in two closely related hosts having different ecological settings, we will test the generality of our conclusions.

Co-leaders : Renaud Mahieux, team "Oncogénèse retrovirale" (CIRI) & David Fouchet, team  "Ecoépidémiologie évolutionniste" (LBBE).
Collaborative teams: Dominique Pontier,  team  "Ecoépidémiologie évolutionniste" (LBBE), Charles Bangham (Imperial College London), Barthélémy Ngoubangoye (International Primatology Center, Franceville, Gabon) and Jean-Nicolas Volf (IGFL, Lyon).
Project duration :
3 years
Financing :
PhD fellowship & consumable money
PhD fellow:
Brice Jegado