T-cell homeostasis in HIV-1 infection

Failure of T-cell homeostasis is an important feature of HIV-1 infection. Substantial evidence indicates that T-cell homeostasis is independent of CD4⁺and CD8⁺subsets, and this may contribute to the decline of CD4⁺T cells to low levels in this disease. Moreover, failure of T-cell homeostasis appears to precede the development of clinically-defined AIDS by approximately 1.5 to 2 years and is thus an important milestone in HIV-1 disease progression. We argue that T-cell turnover and depletion of memory cells in HIV-1 infection can be viewed as the reverse of the process by which immune reconstitution occurs after stem cell transplantation, and that changes in the functional level of T-cell memory may be critical to both processes. An understanding of the relationship between T-cell memory and regeneration of lost T cells may help preserve and/or reconstitute immune system homeostasis in HIV-1-infected individuals.     

Progression of HIV-1 infection

We present data on the distribution of human immunodeficiency virus (HIV-1) proviral DNA in different subsets of peripheral blood mononuclear cells (PBMCs) over an observation period of eight months. Eleven patients with well documented HIV-1 infection were studied. The PBMCs were obtained at two intervals and purified by fluorescence-activated cell sorting (FACS) after staining with FITC-labelled monoclonal antibodies. Varying numbers of FACS-sorted CD4+ cells, CD8+ cells and peripheral monocytes were assayed for HIV-1 proviral DNA (env and gag region) by PCR. Samples from patients at CDC stages II or III had to contain 10(3)-10(4) cells in order to allow detection of proviral HIV-1 DNA. At CDC stage IV, however, HIV-1 DNA was detected in as few as 100 CD4+ T-lymphocytes. In contrast, in peripheral monocytes HIV-1 DNA was not regularly found. CD8+ cells did not harbor detectable amounts of proviral DNA. During an observation period of eight months, the rate of infected CD4+ T-lymphocytes increased significantly in three patients while staying constant in the remaining eight patients. This increase of the infection rate was paralleled by clinical progression in one patient and by a decrease of the absolute number of CD4+ cells in another patient. The percentage of CD4+ cells harboring the viral genome increases in the course of the disease. These results may help to explain the decrease in CD4+ T-lymphocyte counts during HIV-1 infection.     

Immune defence against HIV-1 infection in HIV-1-exposed seronegative persons.

Rare individuals who are repeatedly exposed to HIV-1 through unprotected sexual contact fail to acquire HIV-1 infection. These persons represent a unique study population to evaluate mechanisms by which HIV-1 replication is either prevented or controlled. We followed longitudinally a group of healthy HIV-1 seronegative persons each reporting repeated high-risk sexual activities with their HIV-1-infected partner at enrollment. The volunteers were primarily (90%) male homosexuals, maintaining high risk activities with their known infected partner (45%) or multiple other partners (61%). We evaluated the quantity and specificity of HIV-1-specific T cells in 31 exposed seronegatives (ES) using a IFN-gamma ELISPOT assay to enumerate T cells recognizing epitopes within HIV-1 Env, Gag, Pol and Nef. PBMC from only three of the 31 volunteers demonstrated ex vivo HIV-1-specific IFN-gamma secretion, in contrast to nearly 30% exhibiting cytolytic responses in previous studies. These findings suggest that if T cell responses in ES are induced by HIV-1 exposure, the frequency is at low levels in most of them, and below the level of detection using the ELISPOT assay. Alternative approaches to improve the sensitivity of detection may include use of dendritic cells as antigen-presenting cells in the ex vivo assay and more careful definition of the risk behavior and extent of HIV-1 exposure in conjunction with the evaluation of T cell responses.     

The HPA axis in HIV-1 infection

Several lines of evidence suggest that neuroendocrine abnormalities in general and HPA axis activity in particular occur in both HIV-1 infection and individuals engaging in chronic drug use. For instance, our studies showing attenuated norepinephrine as well as ACTH and cortisol responses to a cold pressor challenge in asymptomatic HIV-1 persons support such a concept. Furthermore, our data on investigations on mirror-star tracing and speech challenges also support the finding that neuroendocrine responses are compromised in HIV-1 infection. Although the mechanisms leading to adverse effects on HPA axis activity in HIV infection are not fully understood, several lines of evidence suggest that a number of mechanisms may be involved, including homologies in molecular structures of various mediators of neuroendocrine activity and HIV-related structures, HIV as a chronic stress model, and virus-induced toxic factors. This article reviews our recent findings in this area and also presents research hypotheses needed for testing and understanding the mechanisms involved in the development of neuroendocrine abnormalities in HIV-1-infected injection drug users.     

HAART is neuroprophylactic in HIV-1 infection

BACKGROUND: To find out about the prophylactic value of antiretroviral therapy on HIV-1-associated subclinical and clinical psychomotor slowing as one marker of HIV-1-associated CNS disease. METHODS: Prospective study with regular clinical and neurophysiologic examination every three months of 1482 consecutive HIV-1-seropositive and AIDS patients seen at our department till June 30, 1999. RESULTS: Antiretroviral therapy has a significant prophylactic value over an individual observation period of ten years with regard to the first, potentially transient manifestation of HIV-1-associated subclinical psychomotor slowing and with regard to the clinical manifestation of motor signs. However, a subgroup of patients is characterized through a second, more sustained manifestation of subclinical psychomotor slowing which cannot be prevented by any type of currently available antiretroviral therapy. CONCLUSIONS: These findings suggest the existence of different pathomechanisms underlying HIV-1-associated brain disease which may in part be effectively prevented, but which in part also escape all antiretroviral treatment strategies in use today.     

Intravenous gammaglobulin treatment in HIV-1 infection

The two main indications for the use of intravenous gammaglobulin--antibody replacement therapy and immunomodulation--are pertinent only for a few scenarios in HIV-1 infection. The role of gammaglobulin in the treatment of HIV-1 infection has changed significantly with the introduction of highly active antiretroviral therapy. Antiretroviral drugs have not only controlled the progression of disease but also had far-reaching effects on HIV-1-induced immunologic aberrations. Complete or partial immunologic reconstitution and prevention of immunologic damage have been the hallmarks of success for highly active antiretroviral therapy. This article addresses the use of gammaglobulin before and after the era of effective antiretroviral therapies.     

HIV-1 infection and cellular metabolism

A recent meeting¹ focused on the role of cellular metabolism in the pathogenesis of human immunodeficiency virus type I (HIV-1) infection and in the disease progression to AIDS.     

Mechanisms of IgE elevation in HIV-1 infection

Serum IgE levels are high in adults and children with HIV-1 infection and could be a marker of poor prognosis. Allergic reactions and adverse reactions to drugs also tend to increase in HIV-1-infected individuals. An imbalance between a "T(H)1-like" and a "T(H)2-like" cytokine profile has been documented in HIV-1 infection. We have demonstrated that HIV-1 gp 120 from different clades is a stimulus for histamine and cytokine (IL-4 and IL-13) release from basophils. Gp 120 acts as a viral superantigen, interacting with the V(H)3 region of IgE to induce mediator release from human Fc epsilonRI+ cells. Human basophils and mast cells express the chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES. By interacting with the CCR3 receptor on Fc epsilonRI+ cells, HIV-I Tat protein is a potent chemoattractant for human basophils and lung mast cells. Preincubation of basophils with Tat protein upregulates mRNA CCR3 and the surface expression of this chemokine receptor. Tat also induces IL-4 and IL-13 release from basophils. Extracellular Tat can influence the directional migration of human Fc epsilonRI+ cells, the expression of chemokine receptor CCR3, and the release of T(H)2 cytokines. Our results indicate two novel mechanisms by which two HIV-1 proteins, gp120 and Tat, trigger the release of cytokines critical for T(H)2 polarization from human Fc epsilonRI+ cells.     

Human-bacteria nitric oxide cycles in HIV-1 infection

The human intestinal tract harbors a complex microbiotic environment containing commensal bacteria and immunocompetent mucosal cells. There is considerable communication between the bacteria and host cells through dietary constituents and metabolic cycles. We propose that in the pathogenesis of acquired immunodeficiency syndrome (AIDS), the human immunodeficiency virus-1 (HIV-1) triggers a change in a coupled transorganism (human-bacteria) nitric oxide interchange cycle, that may influence the biosynthesis and recycling of nitric oxide (NO) in AIDS patients. Normally, nitric oxide (NO) is produced from arginine through nitrate NO(3)(-), which is ultimately eliminated in the urine and feces. In HIV infection, however, the NO(3)(-) is converted into NO and nitrite NO(2)(-) and recirculated in the body, perhaps as a result of concomitant opportunistic bacterial infections and cellular hypoxia. Due to the efficient coupling of the human-bacteria nitric oxide cycles, persistently high levels of nitrite and the free radicals peroxynitrite (ONOO(-)) may occur in AIDS patients, contributing to the etiology of AIDS-related dementia, persistent immunosuppression and Kaposi's sarcoma.     

HIV-1 infection in Juba,Southern Sudan

Thirty years of civil war in the Sudan have resulted in the isolation of the southern provinces which border Central and East Africa. Consequently, little is known about the epidemiology of HIV-1 infection in this region. To estimate the prevalence of HIV-1 infection in southern Sudan and the risk factors associated with disease transmission, a seroepidemiologic survey was conducted in the township of Juba. Study subjects invited to participate in this study included medical outpatients, inpatients hospitalized for active tuberculosis, and female prostitutes. A total of 401 subjects participated in the study. HIV-1 infection was confirmed in 25 subjects. The prevalence of HIV-1 infection was 19% (8/42) among tuberculosis patients, 16% (8/50) among prostitutes, and 3% (9/309) among outpatients. A significantly higher prevalence of HIV-1 infection was found among female prostitutes when compared to female outpatients: 16% (8/50) vs. 2% (4/178), P< 0.001. Correspondingly, the prevalence of seropositives was significantly higher among male outpatients reporting a history of sexual relations with prostitutes during the prior 10 years compared to male outpatients denying relations with prostitutes: 14% (5/37) vs. 0% (0/94), P = 0.001. A history of a sexually transmitted disease (STD) was also associated with HIV-1 infection among male outpatients. The findings of this study indicate that HIV-1 infection is highly prevalent in southern Sudan and that prostitutes and their sexual partners represent a major reservoir of HIV infection in this population. This epidemiologic pattern resembles that seen in the African nations neighboring southern Sudan. Further spread of HIV-1 to northern Sudan could occur because of the movement of military personnel and refugees between the North and South of Sudan. © 1995 Wiley-Liss, Inc.     

Transfusion-transmitted virus infection in HIV-1-seropositive patients

Objectives   To investigate the prevalence, persistence and genome heterogeneity of transfusion-transmitted (TTV) in HIV-1-infected patients, a group at high risk both of contracting blood-borne viruses and having viral persistence relating to immunodepression.
Methods   Plasma samples from 238 HIV-1 seropositive subjects and 226 healthy blood donors were examined for TTV-DNA both by polymerase chain reaction (PCR) using primers from the conserved regions in the N22 clone and PCR using primers deduced from the untranslated region (UTR). Direct DNA sequencing and phylogenetic analysis were used to characterize 27 TTV isolates from HIV-1 patients or healthy controls.
Results   Using PCR with the UTR primers, TTV DNA was detected in a very high percentage (> 80%) of samples both from HIV-1 seropositive subjects and from blood donors. Using PCR with N22 primers, shown to detect viral strains associated with hepatitis of unknown etiology, TTV DNA was found in 103 of 238 (43.3%) HIV-1-infected patients and in 22 of 226 (9.7%) blood donors. There was no difference in the prevalence of the TTV DNA in HIV seropositive subjects with regard to clinical features related to immunosuppression, markers of HCV infection or intravenous drug use; presence of TTV DNA was associated significantly only with male gender ( P = 0.003). Persistent or intermittent viremia was detected in plasma samples taken up over a period of 19 months in all (15 of 15) HIV-infected patients tested.
Conclusions   The persistence and high frequency of infection detected by PCR with N22 primers in HIV-1 seropositive patients suggest that further clinical investigation of immunocompromised hosts will provide information to clarify the pathogenic role of TTV.