Thrombocytopenia in HIV infection

Thrombocytopenia commonly occurs in individuals with HIV disease. However, profound thrombocytopenia, occurring in only 1.5% of cases, is relatively rare. The mechanisms of thrombocytopenia appear to be multifactorial: profound thrombocytopenia in HIV disease is related to an immune destruction either by antiplatelet antibodies or by immune complexes. In addition, a defect in platelet production is quite frequent both in immune thrombocytopenia (ITP) and in mild thrombocytopenia. This impaired platelet production may be due to an HIV infection of megakaryocytes that express a functional CD4 molecule. Treatment of HIV-associated thrombocytopenia is quite similar to that of non-HIV ITP. However, zidovudine increases the platelet count without correlation with its antiviral effect. In animal models and HIV patients, this enhancement of platelet count appears to be due to a stimulation of platelet production, the precise mechanism of which remains unknown. Splenectomy is as effective in severe HIV thrombocytopenia as in non-HIV ITP and has no significant adverse effects on HIV disease.     

T lymphocytes and their cytokines in human immunodeficiency virus (HIV) infection: implications for associated neoplasias

Infection with the human immunodeficiency virus (HIV) results in gradual immunosuppression due to the loss of CD4+ T cells. In the wake of immune system breakdown, infected individuals may acquire multiple opportunistic infections and develop certain malignancies which ultimately account for the vast majority of deaths in these persons. A limited number of malignancies are directly associated with HIV infection and suggest a common tie between these tumors. Inappropriate immune surveillance resulting in insufficient inhibition of virus replication and inadequate control of the growth of transformed cells may contribute to the development of malignancies in HIV-infected individuals. Alternatively, malignancies in HIV infection may be the consequence of immune dysregulation. Cellular immune responses mediated by antigen-specific cytotoxic T lymphocytes (CTL) are of particular importance for immunologic control of viral infections and substantial information has been gathered about theses cells in HIV infection. The goal of this review is therefore to summarize recent findings regarding the cellular immune response to HIV with a particular focus on cytokines released by HIV-specific CTL.     

Activation of CD8+ T lymphocytes through the T cell receptor turns on CD4 gene expression: implications for HIV pathogenesis

T cell activation through the T cell receptor is necessary to achieve a specific and effective immune response. We report here that stimulation of CD8+ T cells through the T cell receptor complex leads to de novo expression of the CD4 antigen on the cell surface that results in susceptibility of CD8+ T cells to HIV infection. In addition, activation of peripheral blood mononuclear cells from HIV-infected individuals results in the appearance of double-positive CD4+/CD8+ T cells, which become infected by endogenous HIV. HIV DNA sequences could be detected in uncultured and sorted mature CD3+CD8+ T cells from HIV+ individuals. These results suggest a new mechanism by which HIV could attack the immune system and may help to explain the CD8+ T cell defects in AIDS patients.     

HIV preventive vaccines. Progress to date

The major conceptual problem for HIV vaccine development has been the lack of information on immune responses known to correlate with protection against HIV infection in humans. In this regard, studies on the natural history of HIV infection and AIDS, especially of people with apparent resistance to HIV infection and of patients with HIV infection who have long term survival without disease progression, may provide important information for vaccine development. In addition, a major concern for the development of broadly effective vaccines has been the extensive genetic variability which is characteristic of HIV. In spite of these unknowns, the first generation of HIV candidate vaccines has been developed and evaluated. HIV candidate vaccines based on the subunit recombinant envelope concept (gp120 or gp160) have been shown to protect chimpanzees from HIV infection on challenge, and have now been evaluated in humans in phase I and phase II trials. These products are well tolerated, and capable of inducing neutralising antibodies, but not cytotoxic T lymphocytes. A second vaccine concept, currently in phase I trials, is based on live recombinant vectors, especially using poxvirus vectors followed by boosting with subunit recombinant envelope vaccines. This concept is theoretically very attractive because preliminary data suggest that these vaccines induce both humoral and cell-mediated immunity. However, no published information is available on the ability of live recombinant vector vaccines to protect chimpanzees from HIV infection. The next step in HIV vaccine development is to proceed carefully to expanded phase II and phase III trials to assess the protective efficacy of these candidate vaccines in humans. These trials will be extremely complex from the logistical, scientific and ethical points of view, and will require close collaboration between clinical, basic science and behavioural researchers, national and international organisations, and the pharmaceutical industry.     

beta-chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques

One of the obstacles to AIDS vaccine development is the variability of HIV-1 within individuals and within infected populations, enabling viral escape from highly specific vaccine induced immune responses. An understanding of the different immune mechanisms capable of inhibiting HIV infection may be of benefit in the eventual design of vaccines effective against HIV-1 variants. To study this we first compared the immune responses induced in Rhesus monkeys by using two different immunization strategies based on the same vaccine strain of HIV-1. We then utilized a chimeric simian/HIV that expressed the envelope of a dual tropic HIV-1 escape variant isolated from a later time point from the same patient from which the vaccine strain was isolated. Upon challenge, one vaccine group was completely protected from infection, whereas all of the other vaccinees and controls became infected. Protected macaques developed highest titers of heterologous neutralizing antibodies, and consistently elevated HIV-1-specific T helper responses. Furthermore, only protected animals had markedly increased concentrations of RANTES, macrophage inflammatory proteins 1alpha and 1beta produced by circulating CD8(+) T cells. These results suggest that vaccine strategies that induce multiple effector mechanisms in concert with beta-chemokines may be desired in the generation of protective immune responses by HIV-1 vaccines.     

Lower genital tract neoplasia in women with HIV infection

Women who are infected with human immunodeficiency virus (HIV) are at greater risk for the development of lower genital tract neoplasia than are HIV-negative women. Among HIV-positive women, those who are more severely immunosuppressed appear to be at higher risk for cervical intraepithelial neoplasia (CIN), also known as squamous intraepithelial lesions (SILs). Women who are HIV-positive also are more likely than HIV-negative women to have multifocal lower genital tract neoplasia. Cervical cancer is one of the most important acquired immune deficiency syndrome (AIDS)--related malignancies in women. Cancer and intraepithelial neoplasia of the lower genital tract can be persistent, progressive, recurrent, and difficult to treat in HIV-positive women. The most effective method for treating SILs has not been determined. Regular performance of Pap smears in HIV-positive women is of critical importance, as is careful examination of the entire lower genital tract. Also, women with high-grade intraepithelial or cervical cancer should be tested for HIV.     

Accumulation of human immunodeficiency virus-specific cytotoxic T lymphocytes away from the predominant site of virus replication during primary infection

Down-regulation of the initial burst of viremia during primary human immunodeficiency virus (HIV) infection is thought to be mediated predominantly by HIV-specific CD8+ cytotoxic T lymphocytes (CTL). This response is associated with major perturbations in the T cell receptor (TCR) repertoire. To investigate the failure of the cellular immune response to adequately control viral spread and replication and to prevent establishment of HIV infection, changes in the TCR repertoire and in the distribution of virus-specific CTL between blood and lymph node were analyzed in three patients with primary infection. By the combined use of clonotype-specific polymerase chain reaction and analysis of the frequency of in vivo activated HIV-specific CTL, it was shown that HIV-specific CTL clones preferentially accumulated in blood as opposed to lymph node. Accumulation of HIV-specific CTL in blood occurred prior to effective down-regulation of virus replication in both blood and lymph node. These findings should provide new insights into how HIV, and possibly other viruses, elude the immune response of the host during primary infection.     

Bioactive fragment of human IL-1beta [163-171] modulates the immune response to synthetic peptides of HIV

The activation of T helper cells specific for viral antigens is critical for antibody production and the generation of cytotoxic T cells during retroviral infection. In this study, we examined the effect of linking HIV peptides with a bioactive fragment of human interleukin-1beta (IL-1beta) (163-171) on the induction of immune response to the peptides. A panel of highly purified synthetic peptides representing defined regions of gp41, Gag and gp120 were used as antigens. Mouse spleen cells primed with the peptide conjugates produced greater proliferation on in vitro stimulation than spleen cells primed with peptide alone. In addition, antibody production as assessed by ELISA was observed after immunization with conjugated peptides but not with peptide alone, indicating B-cell activation. We also found that a high level of IgG2a antibody production correlated with a high level of IFN-gamma production. These findings favor the notion that IL-1beta plays an important role in immune responses. These observations support the formulation and design of synthetic vaccines against HIV using synthetic HIV peptides conjugated with immunomodulators. Such an approach may provide an effective vaccination against other infectious agents.     

Participation of a sialic acid-specific lectin from freshwater prawn Macrobrachium rosenbergii hemocytes in the recognition of non-self cells

Recombinant vaccinia virus (VV) vectors that express the envelope (Env) protein of the human immunodeficiency virus-type 1 (HIV-1) have been previously shown to elicit HIV-specific cytotoxic T-lymphocyte (CTL) and weak antibody responses in non-human primate studies and clinical trials. In first clinical trials, single Env proteins were presented to the immune system by VV recombinants and other vectors, but individuals were not protected against later exposures to heterologous HIV. It is likely that the generation of protective immune responses against diverse HIV will require that vaccines encompass proteins from not just one, but multiple distinct HIV isolates. Here is described the simple construction of numerous new VV, each expressing a unique, truncated, Env protein (VVenv). Mouse experiments were performed to evaluate the ability of these VVenv to elicit immune responses. HIV-1-specific antibodies appeared within one month following one intraperitoneal inoculation of mice with single or mixed VVenv, reaching plateau levels by 4 months. The magnitude of antibody production was poor at the dose of 10(5) p.f.u. VVenv per animal, but improved with increasing doses of VVenv up to 10(7) p.f.u. per animal. The subcutaneous route of VV immunization, previously proven safe in human trials, was also effective for administering VVenv. These results highlight the strengths of recombinant VV constructs as vehicles for the presentation of multiple HIV-1-Env proteins to the naive immune system.     

Coming out: an overlooked concept

WITH CURRENT TRENDS in human immunodeficiency virus (HIV) early intervention moving more toward primary care, more and more advanced practice nurses (APNs) are providing primary care to people with HIV. Because almost half of new cases of acquired immune deficiency syndrome continue to have homosexual or bisexual contact as a risk factor, the APN must be prepared to address the processes that are specific to the psychosocial development of homosexual persons. The most universal of these is coming out. Coming out is a stress-inducing process that can be magnified when combined with HIV infection. Moreover, with growing recognition of the presence and needs of gay and lesbian clients in the health care system, this challenge of helping people cope with the transitions of coming out extends beyond HIV care, from adolescence through old age.     

Comparative analysis of humoral immune responses to HIV type 1 envelope glycoproteins in mice immunized with a DNA vaccine, recombinant Semliki Forest virus RNA, or recombinant Semliki Forest virus particles

The Semliki Forest virus (SFV) system seems to be a useful new approach for generating effective immune responses against HIV-1 in animal models. We evaluated this system by comparing the humoral immune responses raised in mice immunized against the HIV-1 envelope with the SFV system, a DNA vaccine, and a recombinant Env glycoprotein. gp160 ELISA antibody titers (204,800) were highest in the sera from mice immunized with recombinant Semliki Forest virus particles. These sera contained antibodies to the CD4-binding site and recognized linear epitopes on gp120 and gp41 that were also recognized by a pool of sera from HIV1-infected individuals. This demonstrates that the HIV-1 envelope produced in vivo by the SFV system does not fold aberrantly. A low level of neutralizing antibodies against the HIV-1LAI strain was also detected in the serum of one mouse immunized with recombinant SFV particles, suggesting that booster injections should be given to achieve a more effective immune response. SFV recombinant particles induced the strongest humoral responses to the HIV-1 envelope of all the potential HIV env vaccines tested.     

Implications of HIV treatment advances for behavioral research on AIDS: Protease inhibitors and new challenges in HIV secondary prevention.

Protease inhibitor combination therapies can reduce HIV viral load, improve immune system functioning, and decrease mortality from AIDS. These medical developments raise a host of critical new issues for behavioral research on HIV/AIDS. This article reviews developments in HIV combination therapy regimens and behavioral factors involved in these regimens and focuses on four key behavioral research areas: (a) the development of interventions to promote treatment adherence, (b) psychological coping with HIV/AIDS in the context of new treatments for the disease, (c) the possible influence of treatment on continued risk behavior, and (d) behavioral research in HIV prevention and care policy areas. Advances in HIV medical care have created important new opportunities for health psychologists to contribute to the well-being of persons with HIV/AIDS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes in blood coagulation in HIV infection

The human immunodeficiency virus (HIV) infection is becoming more complex. Hemostatic abnormalities occur frequently in the patient with HIV. HIV-related thrombocytopenia (Tr-HIV) is the most common hemostatic disorder with a high morbidity and affects patients from every risk group independently of age, sex, or stage of infection. Two mechanisms are responsible for the Tr-HIV: bone marrow failure and immunological disorders, namely, circulating immune complex deposited on the platelet membrane and the production of autoantibodies directed against platelets. The treatment of choice is zidovudine; other available options are not as effective as zidovudine. In addition, there are some abnormalities in the fluid phase of the coagulation cascade which can produce bleeding or thrombosis in the HIV patient. The most common are a prolonged partially activated thromboplastin time test, the production of a lupic anticoagulant and anticardiolipin antibodies, and several abnormalities in the natural-occurring anticoagulants. The thrombotic thrombocytopenic purpura recently associated with HIV has a clinical presentation and treatment alternatives that closely resemble those for the classical disease. The knowledge of these hemostatic abnormalities in the HIV seropositive patient allows a more rational care of these patients.     

Influence of detergents on the function of cloned potassium channels

The human thymus is a lymphoepithelial organ in which T cells develop during fetal life. After maturation and selection in the fetal thymic microenvironment, T cells emigrate to peripheral lymphoid tissues such as the spleen, gut, and lymph nodes, and establish the peripheral T cell repertoire. Although the thymus has enormous regenerative capacity during fetal development, the regenerative capacity of the human postnatal thymus decreases over time. With the advent of intensive chemotherapy regimens for a variety of cancer syndromes, and the discovery that infection with the Human Immunodeficiency Virus (HIV) leads to severe loss of CD4+ T cells, has come the need to understand the role of the human thymus in reconstitution of the immune system in adults. During a recent study of the thymus in HIV infection, we observed many CD8+ T cells in AIDS thymuses that had markers consistent with those of mature effector cytotoxic T cells usually found in peripheral immune tissues, and noted these CD8+ effector T cells were predominately located in a thymic zone termed the thymic perivascular space. This article reviews our own work on the thymus in HIV-1 infection, and discusses the work of others that, taken together, suggest that the thymus contains peripheral immune cell components not only in the setting of HIV infection, but also in myasthenia gravis, as well as throughout normal life during the process of thymus involution. Thus, the human thymus can be thought of as a chimeric organ comprised of both central and peripheral lymphoid tissues. These observations have led us to postulate that the thymic epithelial atrophy and decrease in thymopoiesis that occurs in myasthenia gravis, HIV-1 infection, and thymic involution may in part derive from cytokines or other factors produced by peripheral immune cells within the thymic perivascular space.     

A cocktail of Mycobacterium bovis BCG recombinants expressing the SIV Nef, Env, and Gag antigens induces antibody and cytotoxic responses in mice vaccinated by different mucosal routes

Recombinant live Mycobacterium bovis BCG strains (rBCG) expressing different human immunodeficiency virus (HIV) or simian immunodeficiency (SIV) antigens could be good candidates for the development of vaccines against AIDS. To develop effective HIV/SIV vaccines, humoral and cellular immune responses directed against multiple antigens may be essential for the control of the infection. In this study we immunized BALB/c mice via different mucosal routes (oral, aerogenic, nasal, and rectal) with a mixture of three rBCG strains expressing, respectively, the entire SIVmac251 Nef protein, and large fragments of the Env and Gag proteins. All routes of immunization studied induced immunoglobulin A (IgA) antibodies against mycobacterial PPD, SIV Env, and SIV Gag antigens in feces and bronchial lavages as well as specific immunoglobulin G (IgG) in serum. Strong, specific cytotoxic responses of splenocytes against Nef, Env, and Gag was observed whatever the mucosal route of immunization. Therefore, mucosal vaccination with a cocktail of rBCG strains induces local, specific IgA, systemic IgG, and systemic CTLs against the three SIV antigens expressed. Rectal and oral routes seemed the most appropriate route of vaccination to be used to protect against SIV infection.     

New mechanisms of viral persistence in primary human immunodeficiency virus (HIV) infection

Viruses, including the Human Immunodeficiency Virus (HIV), have evolved multiple strategies to overcome host immune defenses, allowing them to persist in the host. Molecular and cellular approaches were simultaneously used to provide sensitive and unbiased delineation of the diversity and dynamics of the immune response, and to study the relative compartimentalization of HIV-specific CTL clones in patients undergoing primary HIV infection. This approach revealed that some HIV-specific CTL clones can be deleted in presence of high levels of antigen, a phenomenon analogous to high-dose tolerance or clonal exhaustion described in murine models of persistent viral infections. Also, HIV-specific CTL clones were found to accumulate preferentially in peripheral blood as compared to lymph nodes, even though the large majority of viral replication during primary HIV infection takes place within lymph nodes. These two mechanisms may decrease the effectiveness of the host cell-mediated immune responses, and favor the establishment of virus persistence during primary HIV infection.     

Semen alloantigens and lymphocytotoxic antibodies in AIDS and ICL

More than 90% of people with AIDS develop circulating immune complexes (CICs) and lymphocytotoxic antibodies (LCTAs). Animals infected with HIV, however, never display CICs or LCTAs, and remain healthy. Similarly, HIV-infected people who do not develop CICs or LCTAs also do not progress to AIDS. The appearance of CICs and LCTAs is, however, highly prognostic for AIDS and death. Since HIV infection does not, per se, lead to the development of CICs and LCTAs, other causes are likely. One such cause, for which both epidemiologic and experimental evidence exists, is semen. Semen components include sperm, seminal fluid, lymphocytes, and sometimes infectious agents, including HIV, mycoplasmas, and herpes and hepatitis viruses, all of which independently cause immune suppression. Extensive evidence demonstrates sperm (and various viruses) contains many proteins mimicking the CD4 protein of T-helper cells, while HIV, mycoplasmas, and seminal fluid mimic class II MHC proteins of other lymphocytes. We identify a large number of protein sequences that display such mimicry using computer homology searching, and demonstrate experimentally that sperm antibodies specifically precipitate antibodies against class II MHC mimics such as mycoplasmas, which in turn precipitate antibodies to lymphocyte antigens. These data prove that immunologic exposure to sperm and lymphocytes (as may occur in receptive anal intercourse, needle sharing, or blood transfusions) is theoretically capable of initiating lymphocytotoxic autoimmunity. Such autoimmunity may play a significant role in the pathogenesis of AIDS, and will need to be addressed clinically in high risk individuals regardless of HIV status and regardless of the success of anti-HIV prophylaxis and treatment.     

The efficiency of acute infection of CD4+ T cells is markedly enhanced in the setting of antigen-specific immune activation

Human immunodeficiency virus (HIV) disease in sub-Saharan Africa generally differs from that observed in the United States and other developed countries in that the risk of seroconversion after exposure is greater and the rate of disease progression to AIDS and death is faster. One theory that could in part explain this difference is the increased state of immune activation associated with a relatively high rate of parasite infestation and other infections among inhabitants of these regions. Using a model based on the cellular microenvironment of lymphoid organs, the role of exposure to HIV during a state of antigen-specific immune activation was investigated. Dendritic cells and CD4+ T cells are the major cellular components of the paracortical region of lymphoid tissue, the primary site of HIV replication. We analyzed cocultures of HIV-pulsed dendritic cells that had matured in the presence of tetanus toxoid and CD4+ T cells before and after inducing an antigen-specific response by in vivo immunization with tetanus toxoid. During antigen-specific immune activation, 100 times less HIV was needed to initiate a productive infection. These findings provide a model system to further delineate the relationship between immune activation and the propagation of HIV infection and suggest a mechanism for the epidemiologic observations of an increased ease of developing HIV infection and faster progression for HIV disease in geographic areas where immune activation is prevalent.