HIV hide and seek
Over the years, HIV research efforts have managed to reduce mortality by successfully controlling viral load and replication. However, highly active antiretroviral therapy (HAART) cannot eradicate the virus, and viral rebound is observed after treatment interruption. As a result, lifelong treatment is required to control HIV replication. This is associated with significant side-effects, including drug resistance. The persistence of HIV in treated patients stems from the inability of the immune system to detect the viral reservoir that is insensitive to therapy. The EU-funded HIT HIDDEN HIV project aimed to understand how HIV persists to find ways to achieve complete viral eradication. The key objectives were to elucidate the process of latency and also discover mechanisms of reactivation of latent HIV. Research into the basic mechanisms of HIV post-integrative latency has identified cellular factors (NELF, integrator complex) that work to repress HIV-1 transcription. Inhibition of these proteins should allow transcriptional reactivation of the virus, an approach that could be exploited therapeutically. Another part of the project has focused on the recently identified SAMHD1 immune modulator as the cellular factor restricting HIV-1 infection in myeloid cells. Partners found that the presence of SAMHD1 in myeloid cells allows HIV-1 to escape immune recognition. They have also demonstrated that neutralising antibodies can prevent cell-to-cell transmission of HIV in patients under therapy. In other words, reversal of HIV latency requires activation of cellular factors implicated in viral transcription or inflammation. The identification of the biomarker of HIV persistent cells in vivo was a major breakthrough. Project discovery that CD32a+ CD4 T lymphocytes harbour the elusive HIV-1 reservoir constitutes a crucial step towards specific targeting and elimination of this HIV-1 reservoir. This discovery creates new perspectives for the characterisation, control and eradication of HIV infection. Taken together, the HIT HIDDEN HIV initiative pursued a highly innovative approach for eradicating HIV. The ultimate goal is to confront the infection by awakening the immune system to 'see' and kill the persisting viral reservoir. Given the high cost and difficulty of sustaining existing treatments, a short-term anti-HIV regimen is a more feasible approach, especially for developing countries.
Keywords
HIV latency, HIT HIDDEN HIV, immune recognition, biomarker, CD32a+ CD4 T lymphocytes
