HIV infection and rheumatic diseases--autoimmune mechanisms in immunodeficient hosts.

The recognition of a newly acquired immunodeficiency syndrome (AIDS) in 1981 has had dramatic social and economic implications. Eventually, an epidemic of the viral infection developed with a potential to spread globally. The extraordinary breadth of AIDS research lead to the early identification of the causative agent: The human immunodeficiency virus (HIV) is a member of the lentivirus family and is characterized by its ability to remain latent within the genome of the infected host. The primary targets for the HIV are helper T-lymphocytes and monocytes/macrophages, which results in the progressive destruction of immune functions in the infected hosts. Binding to and entry into the cells is facilitated by a high-affinity interaction of a viral glycoprotein and the CD4 molecule. Signs of the immunodeficient state, manifested as a broad spectrum of opportunistic infections initially dominated the clinical presentations of HIV infected patients. Over the last decade, however, the manifestations of HIV infection have steadily grown and, surprisingly, include many rheumatic syndromes and autoimmune phenomena. The finding that HIV-infected individuals present with a highly progressive form of Reiter's syndrome and psoriasis has challenged our understanding of immune functions in HLA-B27 associated disorders. Obviously, CD8+ T-cells can maintain function despite the depletion of CD4+ helper T-cells. Consistent with the current model of the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus, patients with these syndromes were described to go into remission when CD4+ T-cells were selectively depleted in active HIV infection. There is growing evidence that complex mechanisms arise from the interaction of the HIV and the human host which extend beyond the initial expectation that the virus only kills CD4+ helper T-cells. Indicating yet another aspect of HIV disease, a new syndrome mimicking Sj?gren's syndrome has been encountered in HIV-infected patients and has been named the diffuse infiltrative lymphocytosis syndrome. Dense infiltrates of CD8+, potentially antiviral killer cells, are characteristically found in the salivary glands of patients who express a certain HLA genotype and who are, typically, long-term survivors of the disease. Recent reports have stressed a new mechanism of disease induction in HIV infected patients. Inappropriate induction of potentially destructive cytokines appears to be initiated by the viral infection and the expression of the viral genome seems to be effectively modulated by cytokines. In summary, HIV infection may provide important insights in the pathogenesis of rheumatic diseases co-occurring with HIV infections.(ABSTRACT TRUNCATED AT 400 WORDS)     

Immune activation and neuroinflammation in alcohol use and HIV infection: evidence for shared mechanisms

Background: Emerging research points to innate immune mechanisms in the neuropathological and behavioral consequences of heavy alcohol use. Alcohol use is common among people living with HIV infection (PLWH), a chronic condition that carries its own set of long-term effects on brain and behavior. Notably, neurobiological and cognitive profiles associated with heavy alcohol use and HIV infection share several prominent features. This observation raises questions about interacting biological mechanisms as well as compounded impairment when HIV infection and heavy drinking co-occur. Objective and Method: This narrative overview discusses peer-reviewed research on specific immune mechanisms of alcohol that exhibit apparent potential to compound the neurobiological and psychiatric sequelae of HIV infection. These include microbial translocation, systemic immune activation, blood-brain barrier compromise, microglial activation, and neuroinflammation. Results: Clinical and preclinical evidence supports overlapping mechanistic actions of HIV and alcohol use on peripheral and neural immune systems. In preclinical studies, innate immune signaling mediates many of the detrimental neurocognitive and behavioral effects of alcohol use. Neuropsychopharmacological research suggests potential for a feed-forward cycle in which heavy drinking induces innate immune signaling, which in turn stimulates subsequent alcohol use behavior. Conclusion: Alcohol-induced immune activation and neuroinflammation are a serious health concern for PLWH. Future research to investigate specific immune effects of alcohol in the context of HIV infection has potential to identify novel targets for therapeutic intervention.     

Cytopenias after day 28 in allogeneic hematopoietic cell transplantation: impact of recipient/donor factors, transplant conditions and myelotoxic drugs

Background

Secondary cytopenias are serious complications following hematopoietic cell transplantation. Etiologies include myelotoxic agents, viral infections, and possibly transplant-related factors such as the intensity of the conditioning regimen and the source of stem cells.

Design and Methods

We retrospectively analyzed data from 2162 hematopoietic cell transplant recipients to examine the effect of these factors on overall cytopenias occurring after 28 days in hematopoietic cell transplantation.

Results

Advanced age of the patient, recipient cytomegalovirus seropositivity, unrelated donor status, human leukocyte antigen mismatch and lower doses of transplanted CD34⁺ cells (≤ 6.4×10⁶/kg) significantly increased the risk of cytopenias after day 28. Non-myeloablative hematopoietic cell transplantation had protective effects on anemia and thrombocytopenia after day 28 (adjusted odds ratio 0.76, probability value of 0.05 and adjusted odds ratio 0.31, probability value of <0.0001, respectively) but not on overall or ganciclovir-related neutropenia. This lack of protection appeared to be due to the use of mycophenolate mofetil in the majority of recipients of non-myeloablative hematopoietic cell transplants. Peripheral blood stem cells did not confer protection from cytopenias when compared to bone marrow.

Conclusions

Elderly patients appear to be more prone to cumulative toxicities of post-transplant drug regimens, but non-myeloablative conditioning, optimized human leukocyte antigen matching, and higher doses of CD34⁺ cell infusions may reduce the risk of cytopenia after day 28.     

Confidentiality and disclosure of HIV infection: HIV-positive persons' experience with HIV testing and coping with HIV infection in Latvia

The objective of the study was to explore retrospectively HIV-infected individuals' experience with HIV testing, counselling and the issue of confidentiality in the Latvian context. A qualitative study using grounded theory approach and based on semi-structured in-depth interviews was implemented. Thirteen HIV-positive individuals above 18 were selected, using purposeful sampling, from the 63 HIV-positive individuals registered in Latvia between 1987 and 1997. HIV-infected people are worried that doctors sometimes disrespect confidentiality. Confidentiality was found to be a basic prerequisite for building trusting relationships between an HIV-infected individual and a doctor within the counselling process from the first visit to follow-up counselling and as one of the most important factors of the formation and proper functioning of the physician-patient relationship. Trusting relationships will not be established in situations when an HIV-infected individual is not seen by a doctor as a human being with needs, worries and without understanding his or her situation. Breaches of confidentiality should be seen as shortsighted and can diminish the public's trust in physicians. Counselling should be sensitive to the cultural, historical traditions and prevailing public health practices, social values and political differences in attitude toward the importance of treating someone as a private individual.     

Clinical Assessment and Management of Cytopenias in Lupus Patients

Anemia, leukopenia, and/or thrombocytopenia can occur as a result of non-immune- and immune-mediated mechanisms in patients with systemic lupus erythematosus. Although the differential diagnosis of these cytopenias is broad and warrants a thorough evaluation, lupus disease activity and medications are common etiologic factors. Corticosteroids are the mainstay of initial treatment for immune-mediated hemolytic anemia and severe thrombocytopenia; immunosuppressive agents such as mycophenolate mofetil or azathioprine are often added for their steroid-sparing effects. Rituximab and intravenous immunoglobulin can be considered for refractory cytopenias based on a large body of anecdotal evidence and case series. Newer biologic agents such as belimumab or epratuzumab have yet to be studied specifically in systemic lupus erythematosus–mediated hematologic disorders.     

NIH conference. Immunopathogenic mechanisms in human immunodeficiency virus (HIV) infection.

An understanding of the immunopathogenic mechanisms of infection with human immunodeficiency virus (HIV) is fundamental in developing successful approaches to designing effective therapeutic and vaccine strategies. In this regard, we have investigated the mechanisms by which HIV inserts itself into the human immune system and uses the elaborate cytokine network to its own replicative advantage. We have also shown that the burden of HIV in CD4+ T cells is directly associated with a decline in this cell population in vivo and a progression to disease. Mononuclear phagocytes may play a role in the pathogenesis of HIV infection by serving as reservoirs of the virus. Of note is the fact that monocytes in the peripheral blood of HIV-infected individuals are rarely infected in vivo, whereas infected-tissue macrophages may play a role in organ-specific HIV-related pathogenesis. The role of HIV-specific humoral and cell-mediated immunity in HIV infection is not well understood. However, fine specificity of responses against HIV have been delineated in some in-vitro systems. It is unclear why these responses, particularly HIV-specific cytolytic T-cell responses, diminish over the course of infection and are unable to contain progression of infection.     

Intravaginal practices, bacterial vaginosis, and women's susceptibility to HIV infection: epidemiological evidence and biological mechanisms

Intravaginal practices such as "dry sex" and douching have been suggested as a risk factor that may increase women's susceptibility to HIV infection. These behaviours appear common in different populations across sub-Saharan Africa, where practices include the use of antiseptic preparations, traditional medicines, or the insertion of fingers or cloths into the vagina. We systematically review the evidence for the association between women's intravaginal practices and HIV infection. Although a number of cross-sectional studies have shown that prevalent HIV infection is more common among women reporting intravaginal practices, the temporal nature of this association is unclear. Current evidence suggests that bacterial vaginosis, which is a likely risk factor for HIV infection, may be a mediator of the association between intravaginal practices and HIV. Although biologically plausible mechanisms exist, there is currently little epidemiological evidence suggesting that intravaginal practices increase women's susceptibility to HIV infection. Further research into factors that increase women's susceptibility to HIV will help to inform the design of vaginal microbicides and other HIV prevention interventions.     

Drug-drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A inhibition

The aim of this review is to discuss the effect of pharmacokinetic drug-drug interactions (DDIs) in the antiretroviral treatment of HIV infection. In particular, but not exclusively, DDIs due to the cytochrome P450 3A (CYP3A) inhibitor ritonavir, which is used to increase antiretroviral drug exposure - a technique known as pharmacokinetic enhancement or 'ritonavir boosting'- will be reviewed. The emphasis here will be on the treatment of important co-morbidities common in patients with HIV, including dyslipidaemia, hypertension, tuberculosis and opiate dependence, as well as on the potentially life-threatening interaction between ritonavir and inhalational steroids, and on the effect of acid-reducing agents on some antiretroviral drugs. Finally, further developments with regard to the use of CYP3A-blocking agents to augment the efficacy of antiviral therapy will be discussed.     

Cursed duet: HIV infection and tuberculosis

Tuberculosis remains a health problem of extraordinary magnitude, especially in developing countries. Unfortunately, many of the same countries have the additional burden of a remarkably high prevalence of HIV infection. Because of the inherent capacity of tubercle bacilli to take advantage of deficiencies in cell-mediated immunity, tuberculosis has become an extremely important infectious complication of HIV disease in those developing countries in which the two infections coexist; the same is true, although to a lesser extent, in developed countries among those groups of patients with HIV infection in which there is also a high prevalence of remotely acquired tuberculosis. Prof. Chrétien helped call attention to the link between tuberculosis and HIV infection in France. Now, it is obvious that his cogent observations extend to much of the rest of the world.     

Lentiviral-mediated RNAi inhibition of Sbds in murine hematopoietic progenitors impairs their hematopoietic potential

Shwachman-Diamond syndrome (SDS) is a rare multisystem disorder characterized by exocrine pancreatic insufficiency, multilineage hematopoietic dysfunction, and metaphyseal chondrodysplasia. Bone marrow dysfunction is present in nearly all patients with SDS, with neutropenia being the most common abnormality. The majority of patients with SDS have mutations in the Shwachman Bodian Diamond syndrome (SBDS) gene. We have developed a strategy to examine the consequences of lentiviral-mediated RNA interference (RNAi) of Sbds on hematopoiesis. Here, we report that both Sbds RNA and protein expression can be efficiently inhibited in primary murine hematopoietic cells using lentiviral-mediated RNAi. Inhibition of Sbds results in a defect in granulocytic differentiation in vitro and impairs myeloid progenitor generation in vivo. In addition, short-term hematopoietic engraftment was impaired, which is due in part to reduced homing of hematopoietic progenitors to the bone marrow. Finally, we show that inhibition of Sbds is associated with a decrease in circulating B lymphocytes, despite evidence of normal B lymphopoiesis. These data provide the first evidence that loss of Sbds is sufficient to induce abnormalities in hematopoiesis.     

IFN-alpha: therapeutic options in HIV and HIV/HCV,HIV/HBV dual infection

The antiviral effects of interferon-alpha (IFN-alpha) are well documented for the treatment of hepatitis B or C infections, whereas antiretroviral effects for treatment of HIV-1 infection have been investigated up to now only in small-sized preclinical studies. New preclinical and clinical data on IFN-alpha for HIV, HCV, HBV and especially on co-infections of HIV with HCV or HBV were presented at a symposium of the ConVir conference 2002. This short paper summarizes the presented data on IFN-alpha treatment for HIV and/or HCV or HBV infections.