Effet de l'initiation du traitement antirétroviral sur la diversité virale du VIH

The HIV epidemic has been ongoing for 25 years.  The striking genetic diversity of this virus is a formidable obstacle to the eradication of the pandemic.  Throughout the years, HIV-1 has evolved in more than fifty subtypes and circulating recombinants forms.  This evolution is shaped by selective pressures including the host immune responses and sub-optimal HAART treatment.  In the era of HAART, HIV associated morbidity and mortality has decreased dramatically and significantly improved the life expectancy of infected individuals.  However, treatments are complex, expensive and are associated with toxicity.  When viral replication is not fully contained, drug mutations arise which further complicate treatment options.  This phenomenon is even more complex when taking into account the great genetic diversity of various HIV-1 subtypes.  HIV also has the capacity to persist in different cellular population and thus eradication is extremely difficult to achieve.    Strategies aiming at limiting viral diversity and improving the host immune responses to control HIV replication are needed.  The identification of conserved viral variants could ultimately be useful in vaccine design or as an immunotherapeutic target.  Thus, we have studied the effects early HAART during primary HIV infection has on viral diversity in the C2V5 region of the env gene and on the size of viral reservoir.  We then characterized the selective pressure of ARV on non-B subtype and evaluated drug resistance pathways in non-B HIV genetic background in infected subjects from Mali and Burkina Faso as they initiated treatment.   Our study demonstrated a homogenous viral population during the first weeks post infection.  Viral diversity did increase during the first year to reach +0.23% at the end of the first year post infection.  Patients not initiating treatment exhibited a higher magnitude of viral diversity, and the size of their viral reservoir as determined by the number of infectious units per million PBMC’s also reached higher values.  Our results suggest that early treatment, by slowing viral evolution and size of viral reservoir, could permit strong immune system responses against contemporaneous viruses and could help achieved eradication.  In another study, we followed 801 patients infected with non-B subtype who were about to start antiretroviral therapy.  The majority of these patients were at advanced stages of the infection.  Nevertheless, more than 75% achieved undetectable viral load after 6 months of therapy.  This very encouraging result led us to conclude that antiretroviral therapy was efficient in controlling replication in non-B subtype infection at similar level than in subtype B infection.  In contrast to subtype B infection, we observed different molecular resistance pathways in non-B subtypes, particularly in the AGK/AK/K subtype for which mutations were predominantly associated with the TAM2 pathway.  Although our phylogenetic analysis showed a very closely related viral population in our population, we were able to determine that those mutations were not from a common ancestral virus transmitted in this population but rather were emerging de novo in those patients.  We conducted another study in Mali and our results showed a primary drug resistance frequency of 10%.  We are now conducting phlylogenetic studies to evaluate the prevalence of drug resistance virus transmission in this population.   Our studies suggest that controlling viral replication by treatment could delay viral evolution.  A slower viral diversity could have a beneficial effect on the immune system and could lead to the development of new vaccines or immunotherapeutics strategies.  However, sub-optimal drugs concentrations (poor adherence, toxicitiy) could lead to viral escape and emergence of virus bearing drug resistance mutations which could further be disseminated in the population.

Keyphrases: Primo-infection, HIV-1, Viral evolution, Acute infection, Subtype, Viral variants, Antiretroviral treatment, Drug resistance mutation