Article

INTRODUCTION
AIDS is essentially an infection of the immune system. The complex interactions between virus and immune system have been unraveled through experimental models of AIDS virus infection in nonhuman primates, as well as studies of infected humans. Indeed, with regards to breadth and specificity of immune responses, it is likely that more information has been generated concerning HIV and simian immunodeficiency virus (SIV) than any other viruses in history.Virus-specific CD8+ cytotoxic T lymphocytes (CTLs) have been involved in the control of HIV replication. These CTLs have been found in large numbers in a variety of anatomic compartments in both HIV- infected humans and SIV-infected macaques, including peripheral blood,bronchoalveolar spaces, lympho nodes, spleen, cerebrospinal fluid, skin, semen and both vaginal and gastrointestinal mucosal tissue. Moreover, CTLs can inhibit HIV replication “in vitro”. A central unanswered question is why replication of the AIDS virus, despite the induction of cellular and humoral immune responses after infection, is not contained and leads to progressive and ultimately profound immune suppression. Numerous reasons for lack of immune control have been proposed, but the question is still unclear.

IMMUNE ESCAPE
Selection pressure exerted by humoral and cellular immune responses to HIV is well documented, but its precise contibution to immune failure is still unclear. Selection pressure by neutralizing antibodies can be observed in vitro and is apparent in vivo early in infection, as shown by the emergence of virus that is able to evade early autologous neutralizing antibodies even though it remains neutralization by control sera.

The mechanism of escape may involve changes in envelope. In particular, escape occurs even through single amino-acid mutations in an epitope, at sites essential for MHC binding or T-cell receptor recognition, but may also be influenced by mutations in flanking regions that affect antigen processing. The potentially strong immune selection pressure exerted by CTLs has been particularly well demonstrated in acute SIV infection, in which SIV-infected monkeys generated strong initial CTL responses against an epitope in Tat.Altough the infecting virus was apparently controlled by an effective CTL response against an early-expressed Tat epitope, new viruses with mutations in Tat emerged as this Tat-specific CTL response was being generated, and the variant viruses went on to establish chronic uncontrolled infection. Evidence supporting the influence of CTL selection pressure on this virus comes from population studies examining association between HLA alleles and specific mutations. HLA-associated selection of mutations was found to be predictive of viral load when HIV reverse transcriptase sequences were examined in a cohort of individuals with chronic HIV infection. This evidence of HLA imprinting on a population level supports a significant role of CTL responses in driving HIV evolution. The finding that some alleles preferentially present epitopes to the immune system early in infection, whereas others may not present until later infection, suggests that not all MHC alleles contribute equally to immune control and underscores our lack of understanding of the parameters that influence immunodominance.

DEFECTIVE ANTIGEN PRESENTATION AND LOSS IMMUNOLOGICAL MEMORY Defective antigen presentation would lead to depletion of the circulating T cell pool. Helbert et al suggest that abnormalities in antigen presentation by failing to induce responding T lymphocytes are a key factor in precipitating immunodeficiency. Upon stimulation, T cells switch from CD45RA expression to its small isoform CD45RO. CD4RA cells are immunologically “ naive” whereas CD45RO have a function of memory cells. There is normally a kinetic equilibrium between naive and memory CD4+ T cells ( normally the ratio is at approximatively 1:1), driven by antigen presentation. The presentation defect in HIV infection determines failure of clonal and phenotype switching. CD4+T cells are initially lost from memory pool and later from naive compartment.Possible defects in antigen presentation also include loss of dendritic cells (DC) (early) and monocytes (later), down-regulation of MHC class II molecules on both monocytes and DC and reduced IL-1 secretion.In this pathogenetic model, the size of the naive pool is maintened by re-entering from memory pool. Any shrinkage of the memory cells would therefore result in a gradual decline of the naive cells. Conversely to memory T cells the CD8+ memory T cells are increased from early in infection and substained through symptomatic disease and however CTLs decline during infection. This model is consistent with pattern: the expansion of CD8+ cells is characterized by qualitative changes in their function for the loss of DC , important triggers in stimulating CTLs.

SWITCH FROM Th1 TO Th2 ACTIVITY
Differential production of cytokines by T helper T cells during the immune responses has important regulatory effects on the type of immune response. Clones of Th1 and Th2 cells have been isolated and studied during HIV and AIDS infections. The findings that T cell proliferation and IL-2 production declines while humoral response increases, suggested that a Th1à Th2 switch occurs in the progression of AIDS.

This model suggests the possibility that the progression to AIDS is characterized by IL-2 and gamma-IFN decrease concomitant with increase in IL-4 and IL-10. At this regard Rook et al. also suggest that this Th1/Th2 balance is determined by the action of steroid hormones in the lymphoid tissue at the time of the immunization. On the basis to this hypothesis, glucorticoids bias the system Th2, whereas DHEA acts as a anti-glucorticoid for which T cells have receptors and promotes a Th1 response. A rise in the ratio cortisol/DHEA in the lymphoid tissue could cause a switch from a Th1 to Th2 immune response

NETWORK CYTOKINE
Cytokines as well as other T cell activating factors may be involved in the replication or down-regulation of HIV replication. The relationship between cytokine gene expression and HIV infection seems to hinge an nuclear factor -kappa B ( NFkB). In normal immune response, the induced expression of NFkB contributes to the transcriptional activation of select cellular genes that regulate T cell growth, including IL-2 and IL-2 receptor genes. However, NFkB also binds specifically to the HIV-long terminal repeat (LTR) and activates transcription HIV genes Fig.1. In order to have better insight into the mechanism of HIV infection and HIV induced cytokine genes activation, a panel of model systems has been established to study the regulation of persistent HIV infection in both monocyte and T cell lines. These lines express variable levels of virus depending on their mode of activation. Infection and activation of CD4+ cells or monocytes are associated with the production of a range of cytokines which are themselves related to the HIV expression and replication. Activation of the HIV genome from its quiescent state in infected cells appears to be a central phenomenon in pathogenesis of AIDS. Virus expression can be induced in monocyte ant T lines by mitogenic stimulation. In an experimental model of Fauci, a panel of the recombinant TNF alpha enhanced HIV expression in lymphocyte lines. The activation of replication HIV by TNF is caused by the binding of this cytokine with its surface recptor present at lymphocyte surface Fig.2.

CYTOKINES AND ADC
Recent studies suggest that the production of different cytokines in the nervous central system ( CNS) characterizes the expression of dementia. TGF beta seems to downregulate HIV production in the brain, and it could induce an ihibitory effect on other pro-inflammatory cytokines such as IFN alpha, regulating the brain inflammatory processes and influencing the polarizzation of a Th2 like immune response. Critical issues in the pathogenesis of ADC could be : first, a relationship between dementia and a complex interaction of cytokines with a differential modulation on HIV replication; second, the role of the environment on individual immune responses during the course of HIV disease and the role of new potent antiretroviral drugs in regulating the cerebral viral load.

CONCLUSIONS
here is a general misconception that more is known about HIV than any other virus and that all of the important issues regarding HIV biology and pathogenesis have been resolved. On the contrary, we know only a thin veneer on the surface of what needs to be known. Despite the effectiveness of HAART, new drug targets need to be identified. To understand how HIV can persist in the face of HAART, we need to better understand the cellular reservoirs that mantain the virus during therapy and the mechanism of viral latency. ACKNOWLEDGMENTS I thanks my sons Alex and Marco and dr C. Sbreglia for excellent assistance. I am grateful for laboratory support in the study of cytokines and lymphocytes from my friends M Guarnaccia, L. Atripaldi, A. D'Antonio,D.Ercolini. I also thanks MR Attanasio for help in the preparation of the sera.