Title : Strategies for addressing latent HIV-1 microglial cell reservoirs in adolescents and young adults with Neuro-HIV: Steps towards an HIV cure
Abstract:
Although successful strides have been made in the HIV-1 response, ending AIDS threat by 2030 is a significant challenge, as HIV-1 infections among adolescents and young adult have not decreased fast enough to curb the epidemic. Globally, of the estimated 39.0 million people living with HIV (PLHIV) of which 1.65 millions adolescents and 4.8 millions are young adults. UNICEF reported around 140,000 adolescents newly HIV infections and 27,000 death due to HIV. India is harboring world’s third highest burden of HIV with annual new infection of 66,410 in which youth accounts 16,000 and children 4000. With new antiretroviral regimen and promising prevention tools HIV is experiencing a renaissance, still young population is 21 times at higher risk which threatens zero HIV global goal. Many of the perinatally infected survived children carrying latent virus are in transition to adolescence, while "risk seeking behaviour" of young population leading to casual sex, unsafe sex, experimentation with sexuality and injectable drug use, potentially resulting in increased new infections. These growing adolescents’ faces HIV- Associated Neurocognitive Disorder (HAND) and opportunistic neurological infection which affects their brain development, social and mental health having devastating effect on their life. Although combination antiretroviral therapy (cART) suppresses plasmatic viral pool but not eradicative due to hurdles like very low CNS bioavailability, treatment non-adherence, persisting immune dysfunction leads to health impairments, HIV drug resistance and with cessation of therapy viremia rebounds. 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 the resting memory cluster of differentiation 4 (CD4+) T cells. In early phase of infection, HIV invades the CNS which act as a sanctuary reservoir. Brain microglial are specialized brain-resident immune cells with a decade-long lifespan serve as a stable viral reservoir for latent HIV which are be involved in the emergence of drugs resistance and reseeding peripheral tissues causes HIV-1-associated neurocognitive diseases. Current hurdles in treatment are limitations associated to CNS anatomical barriers, efflux pumps, metabolic enzymes, low oral bioavailability, low CSF: plasma ratio of antiretrovirals (0.002 to 0.63), physicochemical properties of drugs and high protein binding results in persistent proliferation of virus. To ramp up our efforts in the fight against AIDS, there is an urgent need for more concentrated focus on the novel therapeutic strategies which will target and kill these silently proliferating infectious virion with enhanced CNS bioavailability and better understanding of molecular mechanism of latency in glial cell. Hence, various novel strategies for targeting latently proliferating HIV residing in microglial cell will be discussed in the presentation.
