If by some marvel of medicine, doctors could instantaneously halt the spread of HIV, about 35 million people would still be infected with the virus. All of them would need expensive antiretroviral treatment for decades. And in that time, millions of children would still be orphaned by AIDS.
The sombre fantasy seems even more grim given that the virus is still spreading unabated through some high-risk populations, discrimination based on gender or sexual orientation still bolsters infection in many places, and making drugs available to patients requires seemingly never-ending fund-raising. The fight against HIV and AIDS is far from over.
One of the challenges in finding an effective vaccine for HIV/AIDS is the residual virus that remains within the resting memory CD4+ cells of chronically infected individuals. This dormant virus cannot be treated using the currently available drugs. Patients must therefore continue to take expensive antiretrovirals as the risk remains that the virus may reactivate at a later date.
Researchers have attempted to purge these reservoirs to cure HIV. Yet, viral gene expression in latently infected cells is not sufficient to cause the death of these cells if they remain in a resting state. A team of researchers in the US have now found a way of targeting these latent reservoirs for destruction, by boosting immune responses and priming cytotoxic T lymphocytes (CTLs).
Examination of a group of 25 HIV patients who had either started antiretroviral therapy soon after infection or were already chronically infected prior to treatment, showed that the viral reservoirs in chronically infected individuals were dominated by ‘escape mutations’. These mutations allow HIV to evade detection by CTLs. Their overwhelming presence in chronically infected patients compared to those in the acute stage of infection show that the virus adopts such mutations within months of infection. The identification of the escape mutations also explains why simple activation of the latent virus with antiretroviral therapy is not sufficient to clear infection in these individuals.
Following this the researchers exposed CTLs from patients to mixed pieces of HIV proteins. The CTLs were seen to provide a more broad and effective immune response targeting unmutated portions of HIV proteins in vitro. The newly stimulated CTLs targeted residual HIV in both patient groups, with pre-stimulated CTLs showing a greater capacity for the destruction of CD4+ HIV infected cells, than cells which were not initially primed by exposure to HIV protein. This shows that the cells of chronically infected patients can still recognise and eliminate infected CD4+ T cells if stimulated with antigen to give optimal activity.
To test the viability of these findings in vivo the team undertook a small-scale preclinical trial. Using humanised mice carrying T lymphocytes and monocytes/ macrophages derived from patient cells, the team infected the mice with HIV samples from the corresponding patients. Analysis of HIV-levels within these mice showed that pre-exposure of CD8+ CTLs to HIV proteins resulted in significantly less virus in the animals, with 100-1000 fold less viral RNA in the plasma compared to mice treated with CTLs exposed to control proteins.
The possibility of using CTLs primed to target HIV proteins and raise a broader immune response may point to a new direction in HIV vaccine development and offer hope for many patients of a possible cure on the horizon.