Abnormalities and Symptoms of HIV Infection Persons:

During the primary infection with HIV CD4 cell counts decrease and viral loads increase. During the latency stage, CD4 counts with rebound and viral loads will decrease. Eventually (around 10 years later) CD4 count will decrease and viral DNA will increase. Other abnormalities associated with HIV are as follows:

Opportunistic Infections:

Numerous etiologic agents cause debilitating gastroenteritis in immunosuppressed patient populations, including mycobacteria (i.e., M. avium complex and M. genevense), parasites (i.e., Cryptosporidum, Microsporidum), viruses (i.e., rotovirus, Norwalk agent) and typical bacterial pathogens (E. coli variants, Salmonella, Shigella, and Campylobacter).

Lyphomas: AIDS related lymphomas largely originate from B-cells and characterized by extreme clinical aggressiveness. AIDS related lymphoma arises as a consequence of long-term stimulation and proliferation of B lymphocytes.  The lomyphomas associated with HIV infection can be divided into systemic NHL, primary central nervous system lymphomas (PC-NSL), primary effusion lymphoma (PEL or body cavity-based lymphoma (BCB:), and Hodgkin's disease (HD). The vast majority of HIV-1-associated lymphomas are intermediate to high grade B cell neoplasms that fequently presetn at advanced atages, involve extranodal sites, and tend to be associated with a particularly aggressive clinical course. Such patients have a poor prognosis, with a median survival of 6-7 months despite chemotherapy.

Non-Hodgin's Lymphoma (NHL) is listed as one of the diagnostic criteria for AIDS by the Centers for Disease Control. Depsite the introduction of HAART and the clear decline in cidence of certain infections associated with HIV-1 infection, thus far the incidence of systemic HIV-1-associated NHL has not significantly declined. Using the CDC data from a group of transfusion recipients with known dates of HIV infection, the incubation period between infection and the development of lymphomas was approximately 50 months, which is similar to the incubation period for various opportunistic infections also considered as AIDS defining illnesses. The incidence of intermediate/high grade NHL is about 60-100 times greater in AIDS patients than in the general population. NHL is the second most common malignancy associated with AIDS. All population groups at risk for HIV are also at risk for development of lymphoma, in contrast to KS, which is diagnosed primarily in homosexual or bisexual men.

Shift in Th1/Th2 Cytokine Balance:    Cytokines are thought to play a role in the immunologic dysfunction that favors emergence of NHL during the clinical progression of HIV-1 infection. The decline in production of CD4+ T cell type 1 cytokines (e.e., IFN-gamma and IL-2) and the consequence predominnace of a type 2 (e.g., IL-4, IL-10) humoral response likely contribute to host susceptibility. The further the AIDS process develops, the more the immune response moves into the Th2 phase.

High-level CD4+ T cell activation associated with susceptibility to HIV-infection: In a study of 42 high risk seronegative participants (HRSN) and 54 seronegative men who later became HIV seropositive, the HRSN group had higher naive (CD45RO CD27) CD4 and CD8 T cell numbers and lower percentages of activated (HLADRCD38, CD70) CD4 cells.

T lymphocytes of HIV infected people have increased expression of activation markers human leukocyte antigen (HLA)-DR and CD38 and increased proliferation rates (as determined through expression of the nuclear antigen Ki67). This chronic immune activation may potential virus replication either by stimulating secretion of certain cytokines, which induce virus expression, or by maintaining a large pool of activated target cells for HIV that may efficiently support virus replication.

Accumulation of late differentiated cells, CD8+ and CD4+

Overexpression of IL-4: Recently, the analysis of cytokines in the serum of persistently infected seronegative women revealed hypo-expression of the cytokine IL-4. Since the molecular events during HIV-1 infection are associated with a marked increase in levels of IL-4 and IgE in the sera of infected individuals, it has been suggested that AIDS is an allergy. It has also been suggested that very low levels of IL-4 production may abrogate the firus infection. Thus treatment of HIV-1 infected people with drugs that block IL-4 receptors has been suggested as a possible course of treatment.

Pneumonia associated with HIV infection:  Pneumonia remains an important cause of morbidity and mortality in HIV infected patients. A number of factors such as cigarette smoking have been identified that increase the risk of pneumonia. For example, smoking increases the risk of lung colonization due to Pneumocystis jiroveci and depresses phagocytic function of alveolar macrophages in HIF infected patients. Streptoccucus pneumonaie continues to occur with regularity, including infections with antibiotic-resistant isolates. Pneumocystis pneumonia occurs with low incidence in patients receiving HAART, once the CD4 count increases to over 200 ul-1. Legionella pneumophila infections appear to be uncommon in HIV infected patients.

Studies of invasive pneumococcal infections (predominantly pneumonia) indicate that in criticall ill cases, including HIV-seropositive pateints, combination antibiotic therapy is associated with a lower motality than monotherapy.

In the final stages, penetration of the nerve (glial) cells can lead to neuralgia.

Depletion of CD4+ cells: In some cases budding of newly assembled viral particles lead to lysis of an infected cells. In other cases and infected cells survives. The level of CD4 influences this event as gp120 binds to CD4 as it is expressed on the cell membrane. If CD4 level is low as in macrophages, the budding of HIV and subsequent autofusion does not lead to extensive membrane damage and the cells continues to live, producing low level of HIV.

The actual number of HIV infected CD4+ cells in the peripheral blood from asymptomatic persons indicates that only about 1% of the cells are infected. This would clearly not account for the dramtic decrease in T cell counts which can reach levels of about 90%. Various proposals have been put forth to explain this dramatic depletion. 1) One theory is an infected T cell can form a giant syncytium by fusing with many uninfected T cells. 2) another theory is that gp120 which can be found in the fluid due to its unstable noncovalent interaction with gp41 may alone cause such depletion. For example, gp120 could bind to CD4 molecules on normal uninfected T cells thereby interfering with interaction of CD4 with class II MHC molecules on antigen presenting cells or binding of gp120 to CD4 on thymocyties could interfer with the positive selection of class II MHC restricted cells that occurs during T cell maturation.

3) Another possibility is that apoptosis may mediate the death of CD4+ cells. T cells obtained from HIV infected patients undergo spontaneous apoptosis at a greater rate than cells from HIV serongegative subjects. Also, the ex vivo activation of CD4 T cells from HIV infected patients (using a variety of stimuli) consistently enhances apoptosis compared with cells from uninfected subjects. in a phenomenon, termed activation induced cell death (AICD) which occurs only in cells that have been previously activated. Naive peipheral blood T cells from HIV negative patients, when stimulated through the T cell receptor, undergo proliferation, cytokine secretion, and the development of susceptibility to apoptosis induced by Fas ligation. Both in vivo and in vitro, HIV infection is associated with an activate T cell phenotype, increased expression of Fas, enhanced suspectibility to Fas mediated killing, and increased T cell expressed FasL after T cell receptor sitmulation, suggestion a role for Fas/FasL in hIV associated AICD.

• Along these lines the binding of gp120 to CD4 on uninfected cells could results in an inappropriate signal leading to apoptosis or programmed cell death.
• CD95 and its counterpart CD95L have also been proposed to play a major role in CD4+ T cell depletion. T cells from HIV-1-infectged persons show enhanced cell surface expression of DC95 and exhibit increased susceptibility in vitor to CD95 mediated death, which can be induced either by an agonistic anti-CD95 antibody or by a soluble CD95 ligand (CD95L).

Reduction in T_H Proliferative Response: Not only is there a decrease in numbers of T_H cells, but there is also a reduction in the response of these types of cells to antigen. For example, CD4+ T cells from AIDS patients have shown an inability to proliferate in response to certain antigens in comparison to normal cells even where the numbers of the AIDS and control groups were equalized, suggesting that the T cells in AIDS patients may have received inappropriate activating signals, inducing these cells to become anergic or programming them for apoptosis.

Development and function of CD8 T cells: As with CD4 T cells, HIV-1 infection affects CD8 T cell development and function in several ways. Virus impairs thymic output, thus decreasing the number of thymic emigrants. In addition, ongoing viral replication induces a chronic state of T cell activation that leads to clonal expansion, and ultimately clonal exhaustion due to persistent antigenemia. In this way, HIV-1 skews CD8 T cell maturation and leads to an accumulation of activated CD8 T cells that cannot effectively control viremia.

A low level of TCRBV8, CD8+ T cells might be predictive of a more rapid disease progression because an increase in this subtype in HIV-LTNP.

A significant increase in the absolute numbers of T cells coexpressing the gamma delta T cell receptor and CD8 has also been reported in HIV-LTNP patients compared with controls. Also, recovery of gamma delta T cells in subjects receiving prolonged HAART treatment has been reported.

HLA class I Molecules: Possession of certain human leukocyte antigen (HLA) class I molecules (e.g., HLA B35) reportedly predispose patients to rapid disease progression versus others (e.g., HLA B27 and HLA b 58) which endow subjects with longer asymptomatic period. HLA class I molecules are present on the surface of all nucleoated cells where they present short viral peptide fragments called eptiopes, that elicity immune responses from cytotoxic T lymphoctes (CTLs). See natural HIV Immunity

Reduction in B cell response and antibody:  The decline of CD4+ T_H cells eventually affects the functioning of B cells in the humoral response. For example, some AIDS patients can even screen as antibody negative in HIV ELISA tests due to dramatic declines in antibody levels.

Aberrant CD86 expression: has been noted in HIV-1 infection. HIV-1 virions preferentially incorporate CD86 into their membranes and LRs faciliate HIV-1 entry. The heightened immune activation observed in HIV infected individuals enhances CD86 expression, which in turn could induce LR polarization between activated APC and resting T cells, permitting HIV-1 entry into noncycling T cells. The ability of CD86 to induce LR polarization may in part explain in the in vivo susceptibility of resting T cells to HIV-1 infection.

Cytokine Imbalances:  Shift from TH1 activity to TH2 activity:  One hallmark of infection with HIV is progressive T helper cell dysfunction. As HIV disease progresses, the balance of Th1 cytokines (IL-2 and IFN-gamma) that enahnce cellular immunity eventually shift to a Th2 cytokine profile (IL-4, IL_5, IL-6, and IL-10) that promotes humoral respones. The suggestion that helper cell dysfunction is cnetral to the pathogenesis of HIV infection is supported by observations that the Th1 promoting cytokine IL-12, or the use of antagonistic antobides specific for the Th2 cytokines IL-4 and IL-10, restores T cell proliferative responses to recall antigens in HIV infected patients. Early in the disease TH1 activity is high, but as AIDS progresses, there is a shift to TH2 response.

It has been reproted that resistance to apoptosis in HIV and SIV infection is associated with a rpedominance of a Th1 phenotype, arguing that chronic immune activation and a Th2 shift may promote apoptosis. Consistent with this hypothesis, spontaneous apoptosis in cells from HIV infected patients is clocked by the adminstiration of IL-12, IFN-gamma, anti-IL-4, anti-IL-10, and antilymphotoxin, but not by anti-IL-12 therapy. Furthermore, IL-12 protects against the enahced senstivity to Fas mediated apotposis and enhance sensitivty to AICD seen in HIV infected patients.

IL-1 is high which may also account for persistent fevers seen in AIDS patients. Some of the symptoms of dementia in AIDS patients may also be caused by IL-1. Elevated levels of IL-1 along with IL-6 and TNF may also induce proliferation of Kaposi's sarcoma cells.

Both IL-2 and IFN-y have been shown to decrease over time. A reduction of IL-2 also impairs CTL levels since the ability of CD8+T_c cells to generate CTLs requires IL-2. These defects can be restored at least partially by the addition of IL-12 in vitro.

IL-12 p 70 production by PBMCs from HIV-infected patients compared to normal controls has been reported to be defective, consistently after in vitrostimulation using Staphylococcus Aureus (SAC) and less consistently using either LPS or other stimuli. The efect in IL-12 proudction by PBMC of HIV infected patients is relatively specific and not secondary to a generalized inability of their monocytes to produce cytokines or to the overproduction of antogonistic Th-2 cytokines (e.g., IL-4 and IL-10).

Because IL-12 has an important role for macrophage activation, generation and stimulation of cytotoxic T cells and NK cells, immune resposnes to tumors, and generation of IFN-γ producing Th-1 cells, the deficiency of this cytokine in HIV infected individuals may play a role in the progression of immunodeficiency.

Possible role of Dendritic Cells  Tissue culture experiments indicate that DCs can drive the replication of virus in T cells. DCs can either replicate HIV, which then infects T cells in large numbers, or simply capture and directly transmit HIV to permissive T cells. During chronic infection, patients are essentially asymptomatic. Their DCs may well be in an immature or steady state and make take up virions in sizable quantities. Furthermore, immature DCs express several HIV receptors, such as DC4, CCR5, and DC-SIGN, and support virus replication. HIV may therefore exploit immature DCs in an immunologic sense and not just a virologic one. The virus becomes a very efficient form of "self," possibly inducing regulatory T cells and/or deleting HIV reactive T cells from the repertoire.

Alternations in molecules that regulate the apoptotic process

Cells obtained from HIV-infected patients and cells infected with HIV in vitro show changes in the regulation of Fas and Fas ligand. Acute HIV infection of the  promonocytic cell line U937 is associated with viral replication-dependent apoptosis that is characterized by the increased membrane expression of Fas and FasL, by the down-regulation of antiapoptotic proteins Bcl2 and BclXL, and by a concomitant increase in proapoptotic BclXS and Bas. The hypothesis that Fas/FasL interactions may be responsible for HIV-induced apotposis is supported by the observation that soluble Fas receptor decoys block HIV-associated death in U937 cells. This is in marked contrast to the effects of acute HIV infection of T cell lines, which is Fas independent despite increased Fas expression. T cells from HIV-infected patients exhibit both increased Fas receptor expression and enhanced susceptitiblity to Fas-mediated death. FasL is elevated in peripheral blood mononuclear cells (which contains monocytes) from HIV infected patients, and the plasma level of soluble FasL is increased in HIV positive patients and correlates with HIV RNA burden.

The regulation of TNF, TNF receptors, or both is fundamentally altered in HIV infected patients. Elevated serum TNF levels are seen in symptomatic HIV infected patients but not in asymptomatic patients. Furthermore, (1) HIV infection of lymphocytes or monocytes results in TNF production, and (2) TNF activates the transcription factor NFkB, which, in turn, activates HIV transcription, initiating an autocrine loop that results in high levels of TNF production and increased levels of HIV transcription.

Micronutrient Imbalances: Retinol, carotenoids, and alpha-tocopherol plasma concentrations reportedly decrease with HIV infection and advancing immunosuppression.