Immune Responses to HIV Zoran Galic Ph.D. Division of Hematology/Oncology David Geffen School of Medicine UCLA zgalic@ucla.edu August 19, 2014

Innate vs adaptive immunity In response to pathogens, vertebrate immune systems use two interconnected systems: Innate immunity Adaptive immunity

The major cells of innate immunity Big eaters/Always hungry Antigen Presenting Cells (APCs) Proteins eaten by APCs are broken down to small pieces (peptides), which are loaded on special receptors (MHCs) and transported to the cell surface. Peptide+MHC complex can be recognized by a T cell and that interaction can lead to an adaptive immune response.

Adaptive immune response

HIV induces strong cellular and humoral immune responses CTL-cytotoxic T lymphocytes (CD8 killer T cells)

Why is HIV not cleared by the immune system? High mutation rate of HIV HIV latency Compromised immune function, primarily through the loss of CD4 T helper cells

CD4 T cells are depleted in the course of HIV infection

Why are CD4 T cells depleted during the course of HIV infection? HIV-infected CD4 T cells are targeted by the immune response CD4 T cells are lost due to immune exhaustion

Innate immune system vs HIV Innate responses against HIV Rapid and first line of defense against the virus Alert and activate the adaptive immune response Release pro-inflammatory signals Clearance of infected cells Internalize and process the virus to present to T cells to initiate the adaptive response HIV counter-attack The virus can infect members of the innate immune system Innate cells can act as depot and effectively transmit virus Inhibition of function via viral factor release and/or improper immune signals

CD4 T cells vs HIV CD4 T cells responses against HIV Orchestrate adaptive immune response Activated by innate immune system Facilitate CD8 T cell (killer) and B cell activation Provide signals and growth factors for proper immune responses HIV counter-attack Infects CD4 T cells Causes depletion of the CD4 T cell population and thereby removes the “brains” of the immune response Uses surviving CD4 T cells as a reservoir (latent HIV)

B cells vs HIV B cell responses against HIV Directed by CD4 T cell to make antibodies against HIV Antibodies neutralize the virus to prevent spread HIV counter-attack Virus mutates at a very high rate Loss of CD4 T cells results in: Increase in numbers of immature B cells Exhaustion Decreased memory

CD8 T cells vs HIV CD8 T cells responses against HIV Killer arm of the immune system Seek, identify and destroy infected cells Control virus in the initial months of infection HIV counter-attack Virus mutates and escapes Chronic inflammation leads to exhaustion Lack of CD4 T cells: Insufficient signals to activate more killer cells Defective memory Impaired function

Closing Comments APCs, B cells, CD4 and CD8 T cells work together to fight infection HIV perturbs APC function, and kills CD4 T cells This allows secondary “opportunistic” infections to occur, leading to disease/death Vaccines have the potential to halt HIV infection, but thus far an efficacious vaccine strategy has proven elusive A vaccine approach that takes into account all aspects of the immune response will likely have the best chance of success