Cytokines and Chemokines in HIV Infection: Implications for Therapy

HIV infection is associated with both a hyperactivity of the immune system and decreased immune responses against specific antigens. A similar pattern is observed when considering cytokine production in HIV-infected patients. Several cytokines are spontaneously produced at an increased level, whereas other cytokines playing an important role during cell-mediated immune responses are produced at a low level following stimulation. This deregulation of cytokine production may participate to the immune deficiency, both by impairing immune responses and by accelerating CD4+ T lymphocyte destruction. Chemokine receptors have recently been shown to function as coreceptors for the virus, and to govern its cellular tropism. Heterogeneous expression of chemokine receptor may contribute to differences in infectability as well as in rate of progression of the disease between individuals. Better understanding of the role of cytokines and chemokines in HIV infection suggests new therapeutic approaches where administration of cytokines or cytokine antagonists may allow the immune system to function in better conditions, to stimulate antiviral and antiinfectious immune defenses, and to limit viral spread.     

RNAi在HIV感染中的作用

RNAi,作为一种调控特定基因表达的手段,被称为基因组的免疫现象,已成为最近生物医学领域的研究焦点之一。在机体抵抗病毒感染中,RNAi是一种基因水平上的有效的保护性机制。本文就RNAi机制在抵御HIV感染中的研究进展进行了综述。     

Immunity to Human Immunodeficiency Virus (HIV) in Children with Chronic HIV Infection Receiving Highly Active Antiretroviral Therapy

Our objective was to describe the CD4-mediated human immunodeficiency virus (HIV)-specific cell-mediated immunity (CMI) and its virologic and immunologic correlates in children with chronic HIV infection on highly active antiretroviral therapy (HAART). Twelve HIV-infected children on stable antiretroviral therapy with a median level of CD4⁺ lymphocytes (CD4%) of 25.5% and a median viral load (VL) of 786 HIV RNA copies/ml were enrolled in this study. Nine of these children were also cytomegalovirus (CMV) seropositive. Blood mononuclear cells, stimulated with HIV and CMV antigens, were used to measure lymphocyte proliferation and to enumerate gamma interferon (IFN-γ)-producing CD4⁺ cells. HIV CMI and CMV CMI were detected in similar proportions of patients and correlated with each other, although the HIV responses were less robust. HIV lymphocyte proliferation significantly increased with lower HIV VL and showed a trend to increase with higher CD4% and longer time on HAART. The in vitro IFN-γ response to HIV or CMV was not affected by CD4%, VL, or HAART. Pediatric patients with established HIV infection on HAART frequently exhibit HIV CMI despite undetectable HIV replication. We concluded that the association between HIV CMI and CMV CMI indicates that the same factors govern responsiveness to either antigen.     

Effects of Antiretroviral Therapy on Autonomic Function in Early HIV Infection: A Preliminary Report

Background: A prospective study was conducted in human immunodeficiency virus (HIV)-infected patients as they undergo alterations in their antiretroviral therapy (ART) to determine the effect of ART on autonomic function.Methods: HIV-infected subjects who were either 1) naïve to ART and initiating ART, or 2) receiving ART and in HIV virologic failure for at least 4 months and were about to switch ART were enrolled in this study. Autonomic function assessment (cardiovagal, adrenergic, and sudomotor tests) was performed prior to and 4 months after initiating the new ART. Changes in clinical autonomic symptoms and virologic assessment were assessed.Results: Twelve subjects completed the study: 92% male; median age (Q1, Q3) was 41.0 (28.0, 48.2) years; and 50% White/Non-Hispanic. Seventy-five percent were ART naïve while 25% were failing their ART regimen. The median CD4 count was 336.5 (245.3, 372.3) cells/mm³. All subjects achieved an undetectable HIV viral load by the 4-month follow-up visit. The majority of naïve subjects were started on an ART regimen of tenofovir / emtricitabine / efavirenz. There were no significant differences in autonomic function assessment, as measured by cardiovagal, adrenergic, and sudomotor tests, with regards to ART initiation.Conclusion: This is the first study to examine the effects of initiating ART on autonomic function in early HIV infection. This study found no appreciable differences of ART on the autonomic nervous system when ART is initiated early in the course of HIV disease. ART may not contribute to short-term changes in autonomic function.     

Practical Considerations in Gene Therapy for HIV Cure

Despite the success of antiretroviral therapy in suppressing HIV-1 replication and extending the life of HIV-1 infected individuals, this regimen is associated with risks for non-AIDS morbidity and mortality, requires life commitment, and has a high cost. In this context, gene therapy approaches that have the potential to cure HIV-1 infection present a clear option for eradication of the virus in the next decades. Gene therapy must overcome concerns related to its applicability to HIV-1 infection, the safety of cytotoxic conditioning required for cell-based approaches, clinical trial design, selection of gene-modified cells, and the restrictive cost of manufacturing and technology. These concerns are discussed herein in the context of the most relevant gene therapy studies conducted so far in HIV/AIDS.     

Cardiovascular Disease and HIV Infection

The emergence of chronic disease complications in controlled HIV disease has changed the landscape of HIV clinical care. HIV infection confers an increased cardiovascular disease risk, which is thought to be due to a complex interplay of mechanistic factors. While traditional cardiovascular risk factors likely play a role, recent evidence suggests that HIV-associated inflammation and immune activation are important mediators of cardiovascular risk. It is unclear whether established preventative interventions for the general population are applicable to HIV-infected patients, and the need to translate mechanistic knowledge into HIV-specific clinical interventions represents an important priority. Developing strategies to prevent cardiovascular disease in HIV-infected individuals calls for a multidisciplinary approach and represents an opportunity to exert a major public health impact in an at-risk population.     

Sex Differences in HIV Infection

Purpose of Review

This review will outline the multilevel effects of biological sex on HIV acquisition, pathogenesis, treatment response, and prospects for cure. Potential mechanisms will be discussed along with future research directions.

Recent Findings

HIV acquisition risk is modified by sex hormones and the vaginal microbiome, with the latter acting through both inflammation and local metabolism of pre-exposure prophylaxis drugs. Female sex associates with enhanced risk for non-AIDS morbidities including cardiovascular and cerebrovascular disease, suggesting different inflammatory profiles in men and women. Data from research on HIV cure points to sex differences in viral reservoir dynamics and a direct role for sex hormones in latency maintenance.

Summary

Biological sex remains an important variable in determining the risk of HIV infection and subsequent viral pathogenesis, and emerging data suggest sex differences relevant to curative interventions. Recruitment of women in HIV clinical research is a pathway to both optimize care for women and to identify novel therapeutics for use in both men and women.

     

HIV Infection in Women conference

A national conference was held in the US in February 1995 on the issue of human immunodeficiency virus (HIV) infection in women. The conference took place after the Centers for Disease Control (CDC) revised the definition of acquired immunodeficiency syndrome (AIDS) to include invasive cervical cancer. This fact, then, acknowledged that HIV infection in women is not the same as in men. This fact also allowed researchers to focus on women and possibly develop gender-specific prevention and control measures. The conference was the forum to initiate women-specific research efforts. Collaboration in the biological, political, and socioeconomic arenas was strongly promoted. Topics addressed included scientific advancements, program development models, policy and advocacy issues, epidemiological studies, perinatal transmission, counseling, women-controlled prevention methods, and the relationship between violence against women and HIV. The conference was well attended. An address for program and abstract requests is provided.     

Renal Issues in HIV Infection

Kidney disease remains a prominent complication of HIV disease, despite beneficial effects of antiretroviral therapy on the natural history of HIV-associated nephropathy, and on kidney function in general populations of HIV infected patients. Persons of African descent continue to bear a disproportionate burden of severe kidney disease, as is true for the general population. Recently identified genetic variants in the apolipoprotein L1 gene may contribute to this burden. As is also true for the general population, markers of kidney disease, including microalbuminuria, are sensitive predictors of cardiovascular disease and mortality among persons living with HIV. The emerging experience with kidney transplantation also suggests this to be a viable option in selected patients.     

HIV I Infection of Dendritic Cells

Dendritic cells (DC) from human peripheral blood are susceptible to productive and probably to latent infection with HIV-I [18, 29]. Infection of DC also occurs in vivo since in HIV-seropositive individuals Langerhans’ cells of the skin [16] and DC from peripheral blood ([17], in preparation) are infected. In peripheral blood 3–25% of DC, identified as large, low-density cells lacking monocyte markers, are infected as judged by in situ hybridization with an HIV probe. This contrasts with the lower proportion (<0.2%) of other cells infected. DC exposed to HIV in vitro or in vivo fail to present other antigens or mitogens to stimulate T cells [29, 38, 41]. This functional defect in infected DC is not blocked by the presence of soluble CD4 antigen and occurs in the absence of T cell infection suggesting a block at the level of the antigen-presenting cell itself. Infection, depletion and dysfunction of DC in HIV seropositive patients is already present in asymptomatic individuals and this precedes the appearance of T cell defects. We speculate that loss of functional DC may be a fundamental defect leading to a block in recruitment of resting T cells into immune responses.

In contrast to the HIV-induced impairment of antigen presentation by DC, these cells were potent stimulators of responses to the HIV antigens themselves. Normal DC infected with HIV in vitro stimulated primary proliferative and cytotoxic T cell responses ([52], in preparation). These were produced in cells from individuals expressing a range of different MHC types but the cytotoxic cells, once produced, killed autologous but not allogeneic, infected T cell blasts. Primary response to viral peptides can also be produced suggesting that this system may be useful for identifying immunogenic epitopes of HIV using cells from sero-negative, non-immunocompromised individuals.     

Revisiting Immune Exhaustion During HIV Infection

Chronic immune activation is a hallmark of HIV infection, yet the underlying triggers of immune activation remain unclear. Persistent antigenic stimulation during HIV infection may also lead to immune exhaustion, a phenomenon in which effector T cells become dysfunctional and lose effector functions and proliferative capacity. Several markers of immune exhaustion, such as PD-1, LAG-3, Tim-3, and CTLA-4, which are also negative regulators of immune activation, are preferentially upregulated on T cells during HIV infection. It is not yet clear whether accumulation of T cells expressing activation inhibitory molecules is a consequence of general immune or chronic HIV-specific immune activation. Importantly, however, in vitro blockade of PD-1 and Tim-3 restores HIV-specific T-cell responses, indicating potential for immunotherapies. In this review we discuss the evolution of our understanding of immune exhaustion during HIV infection, highlighting novel markers and potential therapeutic targets.     

Progress towards Therapeutic Application of RNA Interference for HIV Infection

HIV-1 infection is the cause of acquired immune deficiency syndrome (AIDS). Highly active anti-retroviral therapy (HAART) has been successful in reducing the rate of progression to AIDS, but a cure has not yet been achieved. New tools are required to delay progression of infection or to block the replication cycle of HIV. RNA interference (RNAi) has the potential to work as a powerful tool against HIV infection. The mode of action of small interfering RNAs (siRNAs) against their target genes is through sequence complementarity, which in turn results in target degradation. siRNAs are showing enormous potential to be used as a therapeutic tool in various diseases; however, this technology still requires refinement before its full potential can be utilized for the development of HIV therapies.     

HIV Infection and Microbial Diversity in Saliva

Limited information is available about the effects of HIV and subsequent antiretroviral treatment on host-microbe interactions. This study aimed to determine the salivary microbial composition for 10 HIV-seropositive subjects, before and 6 months after highly active antiretroviral therapy (HAART), compared with that for 10 HIV-seronegative subjects. A conventional culture and two culture-independent analyses were used and consistently demonstrated differences in microbial composition among the three sets of samples. HIV-positive subjects had higher levels of total cultivable microbes, including oral streptococci, lactobacilli, Streptococcus mutans, and Candida, in saliva than did HIV-negative subjects. The total cultivable microbial levels were significantly correlated with CD4⁺ T cell counts. Denaturing gradient gel electrophoresis (DGGE), which compared the overall microbial profiles, showed distinct fingerprinting profiles for each group. The human oral microbe identification microarray (HOMIM) assay, which compared the 16S rRNA genes, showed clear separation among the three sample groups. Veillonella, Synergistetes, and Streptococcus were present in all 30 saliva samples. Only minor changes or no changes in the prevalence of Neisseria, Haemophilus, Gemella, Leptotrichia, Solobacterium, Parvimonas, and Rothia were observed. Seven genera, Capnocytophaga, Slackia, Porphyromonas, Kingella, Peptostreptococcaceae, Lactobacillus, and Atopobium, were detected only in HIV-negative samples. The prevalences of Fusobacterium, Campylobacter, Prevotella, Capnocytophaga, Selenomonas, Actinomyces, Granulicatella, and Atopobium were increased after HAART. In contrast, the prevalence of Aggregatibacter was significantly decreased after HAART. The findings of this study suggest that HIV infection and HAART can have significant effects on salivary microbial colonization and composition.     

Chemokine Receptors and Chemokines in HIV Infection

Suppression of HIV by chemokines represents a special case in virology and immunology where soluble molecules other than antibodies inhibit infection by a specific virus. The basis for this inhibition is that HIV has evolved to use certain chemokine receptors as coreceptors for entry into host cells. Human genotypes that reduce or prevent coreceptor expression are strongly associated with protection against infection and slower disease progression. We suggest that local production of certain chemokines can produce a similar modulation of coreceptor expression, and mounting evidence indicates that chemokine release is a major determinant of protection from HIV infection. Here we review this evidence and explore future avenues for investigating the role of chemokines in controlling HIV infection.