Peptides presented to CD4 T cells are processed from exogenous antigens (such as defective virus) that are endocytosed by the APC and degraded, and the resulting peptides are displayed on the APC surface in complex with MHC class II molecules. In contrast, CD8 T cells recognize viral peptides in the context of MHC class I molecules. Unlike the peptides that are presented on MHC class II molecules, peptides presented to CD8 T cells on MHC class I molecules are processed from endogenous viral proteins made within the infected cells. Viral proteins made within an infected cell are degraded by the proteasome, transported into the endoplasmic reticulum, and loaded onto MHC class I molecules for expression on the surface of the infected cell.
Since the primary product of HIV replication is defective virus, the bulk of which remains in extracellular spaces, the law of mass action predicts that exogenous rather than endogenously produced antigen will drive the immune response. The class II response, defined by CD4 T-cell stimulation and proliferation, provides the perfect environment for HIV. The low proportion of virus that can effectively infect cells and produce viral proteins for class I presentation cannot compete with the class II response. Consistent with HIV favoring of a CD4 T-cell response is the recent finding that CD8 T-cell responses to simian immunodeficiency virus (SIV) in acute infection are “too late and too little” compared to virus replication: Reynolds et al. showed that although CD8 T-cell responses were present, their timing and magnitude lagged behind those of peak virus production (62
By preferential induction of the CD4 T-cell immune response, HIV can target and replicate in newly activated CD4 T cells. During primary infection, HIV-specific CD4 T cells are the first CD4 T cells to be activated and then infected. This explains why HIV-specific CD4 T-cell responses are present only early in primary infection and are not found in chronically infected, untreated individuals but can be maintained if individuals are treated with antiretroviral agents during the acute stage of disease (45
). Over time, HIV-specific CD4 T cells are continuously used to sustain replicating virus, resulting in the eventual absence of HIV-specific CD4 T-cell responses (40
). When infected, CD4 cells are killed directly by cytopathic effects of replicating virus and by CTL. Yet there are also important mechanisms that trigger CD4 T-cell death in activated, uninfected cells. Apoptosis of uninfected cells through Fas/Fas ligand as a mechanism of CD4 T-cell depletion has been studied extensively. Also, Herbeuval and coworkers (28
) have shown that noninfectious HIV can effectively and specifically trigger CD4 T-cell apoptosis with signaling through the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 and TRAIL ligand. Thus, defective virus can drive virus production via cell activation and can drive T-cell loss by induction of activation followed by apoptosis (28
). Interestingly, the lack of these apoptotic mechanisms in the sooty mangabey may be associated with protection from development of disease (see below).
As CD4 T cells that are specific for the more common HIV antigens decline over the course of disease, the HIV proteins presented change as HIV mutates. Because every CD4 T cell has its own specificity and is activated by a unique peptide, each peptide generated has the potential to activate a CD4 T cell of a different specificity. It has been shown that during chronic infection the specificities of the CD4 T cells devolve to epitopes of lower avidity and frequency (85
; reviewed in reference 21
). With an error rate that changes every amino acid in the HIV sequence every day (54
) and with one in four changes being frameshift mutations (5
), defective virus continuously generates new peptides. Even a single amino acid change in peptide sequence can have a major impact on peptide-MHC binding; recent data have shown that the stability of the MHC class II-peptide complex is key to the ultimate hierarchy of the elicited CD4 T-cell response to antigen (41
). Furthermore, out-of-frame, cryptic peptides made in alternative reading frames of HIV sequences (recently identified for MHC class I presentation [12
]) are likely to exist and increase the repertoire of peptides for MHC class II presentation. Thus, continual generation of mutations and defective viral proteins is a means of generating new peptides that stimulate CD4 T cells of many different T-cell receptor specificities.
Recent studies provide evidence for positive selection of CD4 T-helper epitopes within the virus genome. Using a molecular genetic and statistical approach, Yang and coworkers examined evolution throughout the HIV genome and found that there was widespread adaptive evolution, with a significant number of CD4 T-helper epitopes under positive selection (P
= 0.0001) (56
). Though Yang and coworkers also found evidence for positive selection for CTL and antibody escape within the genome, there were fewer sites than predicted by a random distribution. Taken together, these data argue that HIV actively seeks new CD4 T-helper cell epitopes and minimizes the CTL and antibody sites within the genome.
Peptide diversity has an impact on stimulating CD4 T cells within an individual, but also within a population. There are hundreds of MHC class II alleles in the population as a whole, each with different peptide-binding specificities. Since every individual has a set of MHC molecules with different ranges of peptide-binding specificities and there are multiple variants of each MHC gene within a population as a whole, peptide diversity ensures that very different MHC molecules will find peptides that bind. It is important to note that there has been little success in correlating an MHC class II genotype with protection from disease progression (43