A monoclonal antibody that blockades a little-known molecule on human T-cells, CTLA-4, believed to be responsible for T-cell loss in HIV infection has entered phase I trials in HIV-positive people.
MDX-010, a fully human anti-CTLA-4 antibody, has been developed by Medarex, a New Jersey company, following the observation that cytotoxic T-lymphocyte-associated antigen (CTLA-4) appears to play a number of crucial roles in T-cell loss.
CTLA-4 is not a co-receptor for HIV entry or fusion into T-lymphocytes, but instead acts to regulate a number of mechanisms that govern T-cell numbers. CTLA-4 levels are upregulated as HIV-related immune activation increases, and parasitic infections (another cause of immune activation) also increase CTLA-4 levels.
When HAART is commenced, immune activation is reduced, but CTLA-4 levels do not decline. In individuals with undetectable viral load, CD4 cell increases are directly correlated with CTLA-4 levels: Israeli researchers have found that those with the highest CTLA-4 levels enjoy the smallest CD4 cell increases.
- CTLA-4-positive cells express a higher level of the HIV coreceptor CCR5, so downregulating CTLA-4 expression might also be expected to downregulate CCR5 expression and thus reduce opportunities for HIV infection.
- Individuals with advanced HIV infection have higher levels of CTLA-4, and CD4 cell numbers are inversely correlated with CTLA-4 levels
- The ability of HIV-infected individuals to mount an HIV-specific T-cell response declines as CTLA-4 levels go up
CTLA-4 expression increases the risk that cells will become infected with HIV, because it responds to antigen presenting cells that are attempting to recruit T-cells by activating those T-cells. When the antigen being presented is HIV, this is fatal for T-cells. Several test tube studies have shown that when CTLA-4 is blocked by an antibody, HIV cannot spread to uninfected cells.
Isreali and US researchers have suggested that CTLA-4 offers an attractive therapeutic target, with a number of possible applications:
Medarex is particularly interested in the potential of their antibody product to boost HIV –specific immune responses.
"The ability to boost the potency of the cellular immune response against
HIV could be crucial in allowing patients to control the virus with their own
immune systems," said Dr. Israel Lowy, Director of Infectious Diseases
at Medarex. "If MDX-010 can boost anti-HIV immunity, this may allow patients
to require less medication, or perhaps be weaned from the necessity of
lifelong HAART, with its attendant challenges of treatment toxicities and
requirements for strict adherence."
Medarex is recruiting 18 treatment-experienced US patients with detectable viremia to receive two consecutive monthly doses of the antibody in a dose escalation study designed to test safety and efficacy
- Blockade of CTLA-4 could reduce CCR5 expression, increasing the window of opportunity for fusion inhibitors such as T-20 and T-1249 to act against HIV’s gp41 region as it prepares for fusion. When CCR5 expression on the cell surface is low, HIV’s gp41 region remains exposed for much longer whilst the virus seeks to engage with multiple receptors on the surface of the cell.
- Blockade of CTLA-4 could enhance the HIV-specific immune response being elicited by therapeutic vaccines
- Reducing CTLA-4 levels could aid immune reconstitution in treatment-experienced patients, permitting treatment interruptions with greater safety
Leng Q et al. CTLA-4 upregulation during HIV infection: association with anergy and possible target for therapeutic intervention. AIDS 16: 519-529, 2002.
Riley JL et al. Modulation of susceptibility to HIV-1 infection by the cytotoxic T lymphocyte antigen 4 costimulatory molecule. Journal of Experimental Medicine 191 (11): 1987-1997, 2000.