Current HIV Research - Volume 4, Issue 2, 2006

HIV-1, the causative agent of AIDS, is an obligate intracellular parasite that has both evolved to invade the complex human system and adapted to utilize the host machinery for its own propagation. A dynamic interaction between the virus and the host systems can be observed at every step of HIV-1 life cycle. Host factors are involved not only for mounting antiviral responses but are also hijacked by the virus to assist in its replication. The host factors are necessary for viral replication during entry, reverse transcription, nuclear import, integration, transcription, nuclear export, translation, assembly and budding. All retroviruses including HIV-1, are species-specific and the replication of the retroviruses is blocked in the restrictive host by the action of "host restriction factors". These restriction factors act as barriers to retroviral replication at various stages within the infected cell of a restrictive host. Nevertheless, HIV-1 virus has learned to subvert these antiviral responses and successfully propagate within the permissive host environment. This review article describes identification and mechanism of action of several pro- and anti-HIV-1 host factors. It is likely that we are just beginning to get a glimpse of an ongoing complex battle between the HIV-1 and the host, understanding of which should provide valuable information for the development of novel therapeutic strategies against HIV-1...

Human immunodeficiency virus type 1 (HIV-1) has a small, multifunctional genome that encodes a relatively large and complex proteome. The virus has adopted specialized post-transcriptional control mechanisms to maximize its coding capacity while economically maintaining the information stored in cis-acting replication sequences. The conserved features of the 5' untranslated region of all viral transcripts suggest they are poor substrates for cap-dependent ribosome scanning and provide a compelling rationale for internal initiation of translation. This article summarizes key experimental results of studies that have evaluated HIV-1 translation initiation. A model is discussed in which capdependent and cap-independent initiation mechanisms of HIV-1 co-exist to ensure viral protein production in the context of 1) structured replication motifs that inhibit ribosome scanning, and 2) alterations in host translation machinery in response to HIV-1 infection or other cellular stresses. We discuss key issues that remain to be understood and suggest parameters to validate internal initiation activity in HIV-1 and other retroviruses.

Cross-species transmission of retroviruses poses a threat to mammalian species. Zoonoses have given rise to devastating diseases because the host organism is not prepared to resist a new pathogen. Mammals have developed several layers of defense against viruses, including an intracellular antiretroviral defense, a part of innate immunity. Retroviral restrictions had been studied for decades using murine leukemia virus in mice, however it has become clear that primates too have intrinsic mechanisms to ward off infections by retroviruses. Several of these antiretroviral restriction mechanisms have recently been identified, with two particularly well described factors being members of the tripartite motif (Trim) and APOBEC families. Both systems provide a strong barrier against lentiviral infections. The viruses have developed countermeasures that allow them to replicate despite the host factors. This review discusses our current knowledge of this ancient battle between mammalian hosts and their retroviral opponents.

Dendritic cells (DCs), the professional antigen presenting cells, are critical for host immunity by inducing specific immune responses against a broad variety of pathogens. Remarkably the human immunodeficiency virus-1 (HIV- 1) subverts DC function leading to spread of the virus. At an early phase of HIV-1 transmission, DCs capture HIV-1 at mucosal surfaces and transmit the virus to T cells in secondary lymphoid tissues. Capture of the virus on DCs takes place via C-type lectins of which the dendritic cell-specific intercellular adhesion molecule-3 (ICAM-3) grabbing nonintegrin (DC-SIGN) is the best studied. DC-SIGN-captured HIV-1 particles accumulate in CD81+ multivesicular bodies (MVBs) in DCs and are subsequently transmitted to CD4+ T cells resulting in infection of T cells. The viral cell-to-cell transmission takes place at the DC-T cell interface termed the infectious synapse. Recent studies demonstrate that direct infection of DCs contributes to the transmission to T cells at a later phase. Moreover, the infected DCs may function as cellular reservoirs for HIV-1. This review discusses the different processes that govern viral piracy of DCs by HIV-1, emphasizing the intracellular routing of the virus from capture on the cell surface to egress in the infectious synapse.

Antibody neutralization would be a major way to prevent HIV infection and disease progression, but the complex relationship between host and pathogen makes tough to achieve this target through immunogens based on viral envelope proteins. Autoimmunity has been associated to bacterial and viral diseases, as a consequence of inflammatory response to pathogens; it may eventually lead to harm host cells and organs. However, autoimmune-like responses have also been observed in HIV-infected patients, raising many questions about their clinical significance. Recent studies have elucidated both similarities and differences between anti-self responses in HIV infection and autoimmune diseases, identifying new molecular players that might enhance immune protection to HIV and/or modulate the clinical progression of the established infection. This paper will present the current knowledge on auto-antibodies observed in HIV infection, their putative mechanisms of generation and their possible implications for immune therapy.

Sterilising immunity against HIV-1 infection, whilst ideal, appears an unrealistic vaccination goal in the short term. More achievable is slowing the progression to disease and decreasing transmission by mounting strong T cell and neutralising antibody responses to maintain low viral loads. However, in both acute and chronic infection, mutant virus is selected to escape both arms of the adaptive immune system. Each mutation away from wildtype virus likely incurs at least some reduction in replicative capacity ("fitness") of the virus. Rapid reversion to wildtype of some immune escape mutations upon transmission, suggests fitness costs may be significant. HIV-1 Envelope is unique in that it is subject to both neutralising antibody and cell-mediated immune responses. Although Envelope is variable between strains, considerable serial pressure and mutational escape from both neutralising antibody and cytotoxic T lymphocyte attack may result in impaired structure and function. This could ultimately be exploited in HIV vaccine design.

HIV-1 infection persists despite long-term administration of highly active antiretroviral therapy (HAART). The mechanism of this persistence appears to result primarily from viral infection of CD4+ T-lymphocytes that have the ability to duplicate and revert into a quiescent state. These infected resting cells are long-lived and evade immune surveillance or clearance. The inability to eradicate this class of cells, bearing the viral DNA, suggests life-long persistence of virus in HIV-1-infected individuals, even if HAART were administered for decades. This review discusses the origins and mechanisms accounting for stability of these latent HIV-1 cellular reservoirs. It further provides an overview of recent clinical trials aimed at their eradication. There have been a limited number of immune activation (IAT) trials directed at HAART-persistent, viral reservoir eradication. These trials have not resulted in purging of these highly stable viral reservoirs though results from such efforts suggest partial effects. The properties of novel compounds that might be included into IAT eradication protocols are continuing to be evaluated and their potential for inclusion into future IAT trials will be discussed.

Sexual behavior can threaten the physical and social well-being of young people in the United States in a variety of ways, as it can put them at risk for infection with the human immunodeficiency virus (HIV), other sexuallytransmitted diseases (STDs) and unintended pregnancy. This review describes the current extent of HIV infection in American adolescents, identifies and characterizes particular high-risk groups and risk-bearing and protective behaviors, and identifies barriers to adopting preventive behaviors and using health care services. Our main focus is to present findings from intervention research; we summarize the effects of strategies that operate at the individual level (i.e. biomedical or behavioral, in and outside of the clinic) and environmental level (i.e. family, school and community behavioral) to influence behavioral change and the prevention of HIV infection. Overall, even though abstinence eliminates the risk altogether and the use of condoms can effectively reduce the risk of sexual transmission of HIV, adolescents do not optimally employ these practices. Various approaches to counseling by providers and other behavioral interventions aimed at reducing high-risk sexual behavior have been effective, but have met with limited and short-lived success. Among the areas receiving inadequate attention to date have been the link between biomedical and communitybased behavior change interventions and the correspondence of biologic and behavioral outcomes. These areas are explored and directions for future research are suggested.

Background. Multiple factors have been previously described which could influence adherence to HAART. Our objective is to determine the fundamental factors which influence adherence to highly active antiretroviral therapy in our population. Methods. A cross-sectional study was made selecting 143 outpatients attending our hospital HIV unit. 22 factors were recorded which could influence adherence to treatment (covering individual factors, the illness itself, the therapeutic regimen and the medical team). Adherence was estimated by the combination of two methods (self-report and pharmacy data); statistical analysis was performed using univariate and multivariate methods. Results. 96 patients (67.13%) had good adherence and 47 (32.87%) did not. Only 3 of the 22 factors studied were significant and independent factors related with adherence: employment, housing situation and degree of treatment acceptance. Conclusions. we have found some differences regarding HAART adherence in our population compared with previous studies. Psychosocial and behavioral factors were the principal ones. We must try to detect patients at high risk of nonadherence in order to take therapeutic decisions properly, try to reinforce adherence and modify the factors associated with poor adherence.

Previous analyses of HIV-1 surface glycoprotein indicate that both the V1/V2 region and the interaction of gp120 with CD4 influence the accessibility of the V3 region on gp120. In this study we investigated the accessibility of the V3 region of HIV-2 recombinant gp125 proteins using V3-specific mAbs (7C8 and 3C4) and analyzed the binding kinetics of soluble CD4 (sCD4) to recombinant HIV-1 gp120 and HIV-2 gp125 proteins by surface plasmon resonance (SPR) analysis. Our results indicated that 7C8 recognized monomers of gp125 and gp125 Δv1v2, (lacking the V1/V2 region) while 3C4 was sensitive to the conformation of gp125, recognizing only oligomers of gp125 Δv1v2. Furthermore, SPR analysis of 7C8 binding to gp125 demonstrated that the deletion of the V1/V2 region did not increase the accessibility of the V3 region in gp125 Δv1v2. Comparative SPR analyses of sCD4 binding HIV recombinant surface glycoproteins revealed a lower affinity of sCD4 to gp125 as compared to gp120. Moreover, the analyses suggest that conformational changes only occur in HIV-1 gp120 upon interaction with CD4. We hypothesize that the V3 region is accessible in HIV-2 gp125 and thus may not require interaction with CD4 to induce conformational reorientation of the V1/V2 region.

Takotsubo cardiomyopathy (in Japanese language "takotsubo" is a fishing pot with a round bottom and a neck that is used for trapping octopuses) is a new syndrome, which is characterized by transient left ventricular dysfunction and by a typical left ventriculogram showing transient extensive akinesis of the apical and mid portions of the left ventricle with hypercontraction of the basal segment, from which this disease takes its name. Since 1990 sporadic cases of takotsubo cardiomyopathy were reported by Japanese authors, and only a few European reports are available. We report a case of takotsubo-like left ventricular dysfunction in an human immunodeficiency virus (HIV)-infected caucasian patient.