Page 16 - AIDSBK23C

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Mechanisms that contribute to continued HIV-associated lymphocyte apoptosis include chronic
immunologic activation via gp120/160 of the CD4 receptor, enhanced production of cytotoxic
ligands or viral proteins by monocytes, macrophages, B cells, and CD8 cells, and direct infection
of target cells by HIV resulting in apoptosis. HIV envelope glycoprotein induces chemokine
CXCR4-dependent autophagy of uninfected lymphocytes, which is required for caspase-
dependent, apoptotic cell death and caspase-independent, nonapoptotic cell death. Apoptosis of
lymphocytes is increased with progression of HIV disease and diminished with effective
antiretroviral therapy.[63,64]
Subsets of the CD4+ lymphocyte population are important in determining the host
response to infection. The subset known as TH1 (T helper 1) is responsible for directing a
cytotoxic CD8+ T-lymphocyte response, but the TH2 (T helper 2) subset of CD4+ and CD8+ T-
lymphocytes diminishes the cytotoxic lymphocyte response while increasing antibody
production. Persons infected with HIV who have a dominant TH1 response tend to survive
longer. CD8+ lymphocytes can inhibit HIV infection though both HLA-restricted cytolysis as
well as suppressive activity mediated through release of multiple suppressive factors collectively
termed CD8 antiviral factor (CAF).[55]
The switch from a TH1 to a TH2 response has been suggested as a factor in the
development of AIDS. CD4+ lymphocytes produce IL-2 and IFN-gamma in a TH1 response,
and IL-4 and IL-10 as part of a TH2 response. Production of interleukin-5 (IL-5) and interferon-
gamma (IFN-gamma) by CD4+ and CD8+ T-lymphocytes expressing CD30 is associated with
promotion of B-lymphocyte immunoglobulin production.[65,66] The imbalance in the TH
response to a predominantly TH2 response is mediated by HIV proteins gp120 and Tat, which
trigger the release of cytokines necessary for a TH2 response. These HIV proteins stimulate
mast cells and basophils. The Tat protein upregulates chemokine receptor CCR3 on mast cells
and basophils and renders them susceptible to infection by CCR3 tropic HIV. Increased serum
IgE levels suggest that a TH2 response has occurred and predict a poorer prognosis.[67]
The subset of helper T cells known at TH17 cells may become infected with HIV. All
TH17 cells express the chemokine receptor CCR6, and a subset of those are also CCR5 positive
are preferentially infected with HIV. Though most TH17 cells are not directly infected by HIV,
they tend to diminish during the course of HIV infection. TH17 cells are found in the
gastrointestinal tract lamina propria and aid in mucosal immunity. Depletion of TH17 cells may
predispose to opportunistic infections involving the gastrointestinal tract, Long-term
antiretroviral therapy can restore Th17 cells in the gastrointestinal tract, which may be associated
with better prognosis.[68,69]
The CD8+ lymphocyte response to early HIV infection is not sufficient to contain
continued viral replication. Though the “founder” clone of HIV may be reduced or eliminated
by a CD8 cytotoxic response, HIV mutations introduce clones, so-called “escape mutants”, that
continue the infection. In acute HIV infection, a limited number of specific CD8 T cell
responses occur to suppress viremia. The efficacy of this early CD8 cell response determines the
set point of plasma viremia that predicts the subsequent course of HIV infection. Over time,
more varied and robust CD8 T cell responses occur, but without a change in the control of viral
replication or further reduction in the viral set point. Thus, CD8 cell responses in acute HIV
infection appear able to suppress viral replication, but responses generated in the chronic phase
of HIV infection are impaired.[70]
Tissue mast cells may form a reservoir for HIV infection. Progenitor mast cells (prMC)
are derived from pleuripotential CD34+ stem cells. The prMC express CD4, CXCR4, and CCR5