Current HIV Research - Volume 2, Issue 3, 2004

HIV-related morbidity and mortality have been dramatically improved in populations treated with combination antiretroviral therapy. Although it is widely recognized that adherence to the antiretroviral medication regimens is vital to treatment success, rates of adherence to the regimens are often poor. There is a large body of research exploring the problem of adherence to antiretroviral medications. The literature is, to date, dominated by reports identifying factors that are predictive or associated with antiretroviral adherence. Adherence is increasingly understood as a dynamic behavior influenced by a matrix of interrelated factors that change over time. Preliminary reports suggest varying degrees of success with strategies designed to improve adherence. Multifaceted strategies appear to be the most promising; however, there are few controlled studies substantiating the effectiveness of these approaches and the mechanisms by which the interventions promote adherence are not well understood. More well powered, rigorously evaluated antiretroviral adherence intervention trials are urgently needed. Further, problems in the field exist because of limitations in the available adherence measures. This paper provides a comprehensive review and analysis of the state-of-thescience of this body of work. Despite substantial attention to antiretroviral adherence in recent years, there remain significant gaps in our understanding.

In the current era of highly active antiretroviral therapy (HAART), the prevalence of HIV-associated non-Hodgkin lymphoma (H-NHL) is not as high as in the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic, but still remains above that of non-HIV-infected individuals. Therefore, the epidemiology suggests that the pathogenesis of H-NHL may be multifactoral, involving the interaction of the immune system with HIV or other pathogens. Although HIV is a retrovirus, it is not characterized with the typical oncogenic potential associated with insertional mutagenesis. HIV integration occurs as a necessary step in the life cycle allowing for replication and transcription of the viral genome to take place. While HIV is thought to integrate randomly, more recent studies have suggested that integration occasionally occurs in a less random fashion. While the majority of H-NHL may be secondary to immune dysfunction, this non-random integration may be a factor leading to pathogenesis of a small subset of H-NHL since the pathways involved in malignancies usually require an accumulation of abnormalities leading to proliferation and transformation. A common element among lymphomas in this setting of immune dysfunction is the inability to control a pathogen that acts as an ongoing immune activator. Thus, an increased risk of H-NHL emerges from the combination of immunodeficiency, increased immune activation and possible HIV insertional mutagenesis. The focus of this review will be on the role viral pathogenesis plays in oncogenic transformation.

Recent advances in our understanding of the cellular and molecular mechanisms of HIV-1 entry provide the basis for novel therapeutic strategies that prevent viral penetration of the target cell-membrane, while reducing detrimental virus and treatment effects on cells and prolonging virion exposure to immune defenses. A number of potential sites for therapeutic intervention become accessible during the narrow window between virus attachment and the subsequent fusion of viral envelope with the cell membrane. Initial approaches considered for prevention of HIV-1 entry included the use of natural ligands, small-molecule inhibitors and / or monoclonal antibodies, which could interfere with gp120-CD4 and / or gp120-CXCR4 / CCR5 interaction. Others avenues pursued were the use of agents that interfere with the conformational changes of gp120 or gp41 leading to subsequent fusion of viral and cellular membranes. More recently, strategies have emerged that involve inhibition of thiol / disulfide oxidoreductases (factors which facilitate Env transition from an inactive to a fusion-competent conformation) to block redox exchange, thereby impeding the entry process. This review provides a summary of the cellular and viral factors mediating the HIV-1 entry process, with an emphasis on novel therapeutics targeting Env-receptor / coreceptor interaction, Env conformational change and the membrane fusion process.

Immune Restoration Diseases (IRD) are a collection of atypical 'opportunistic infections' and inflammatory diseases seen in human immunodeficiency virus (HIV) patients after HIV viraemia is suppressed by highly active antiretroviral therapy (HAART). IRD probably reflect dysregulated immune responses against pre-existing infections by opportunistic pathogens, with different immunopathological mechanisms for different pathogens. For example, mycobacterial IRD are associated with delayed type hypersensitivity (DTH) responses to mycobacterial antigens, whereas patients who experience cytomegalovirus (CMV) IRD have elevated plasma levels of soluble CD30, a marker of a T2 cytokine environment expressed by activated CD8 Tcells. As IRD are often compartmentalised to organs, monitoring serological markers such as pathogen-specific IgG antibody, may be informative, as demonstrated for CMV and hepatitis C virus (HCV)-associated IRD. Genetic studies have provided evidence of distinct immunopathological mechanisms and inherited susceptibility to IRD associated with mycobacterial and herpesviridae infections. The expansion of HAART in the developing world where many HIV patients have low CD4+ T-cell counts and high rates of concomitant infections will place a large number of patients at-risk of developing IRD. It is therefore important to understand the immunopathology so that prevention, diagnosis and treatment can be improved.

Neutralizing antibody titers have been correlated with protection following vaccination against many viral pathogens. The logical target of protective antibody responses elicited by potential HIV vaccines should be the viral Env spike on the surface of the virion. However, the potency and titers of neutralizing antibodies that arise during HIV infection are generally discouragingly low and the antibodies that do arise recognize mainly autologous virus. This is thought to be a result of a combination of immunodominance of hypervariable regions of the Env protein that can easily escape neutralization, antibody reactivity to gp160 “decoy”' protein in cell surface debris or monomeric gp120, conformational constraints within the Env trimer that create unfavorable antibody binding conditions and extensive glycosylation of the exposed regions of Env within the trimer. This review will describe current knowledge regarding glycosylation as a mechanism of neutralization resistance and discuss experimental approaches used to overcome this resistance. Part of the strategy toward development of an optimally immunogenic Env spike will likely require modification of Env glycosylation.

The Vpu protein is the smallest of the proteins encoded by human immunodeficiency virus type 1 (HIV-1). This transmembrane protein interacts with the CD4 molecule in the rough endoplasmic reticulum (RER), resulting in its degradation via the proteasome pathway. Vpu also has been shown to enhance virion release from infected cells. While much has been learned about the function of Vpu in cell culture systems, its exact role in HIV-1 pathogenesis is still unknown. This has been primarily due to the lack of a suitable primate model system since vpu is found only in HIV-1 and simian immunodeficiency viruses isolated from chimpanzees (SIVcpz), and three species of old world monkeys within the genus Cercopithecus. Several laboratories have developed pathogenic molecular clones of simian-human immunodeficiency virus (SHIV) in which the tat, rev, vpu and env genes of HIV-1 are expressed in the genetic background of SIV. The availability of such clones has allowed investigators to assess the role of Vpu in pathogenesis using a relevant animal model. This review will focus on the current understanding of the structure-function relationships of Vpu protein and recent advances using the SHIV model to assess the role of Vpu in HIV-1 pathogenesis.

Superinfection is defined as infection by a second virus during an immunologic steady state, following infection by a primary virus. It is now well established that superinfection with HIV-1 occurs in humans. Detection of an increasing number of circulating recombinant forms, which result from infection of a cell by two or more clades, suggests that superinfection occurs more frequently than previously thought. The second virus (from a different clade or the same clade as the primary virus) can superinfect some time after the first and this is associated with rapid viral rebound and immune decline. Primary infection with a specific clade appears not to provide cross-protection against superinfection with a different clade or the same clade. Estimating the overall impact of HIV-1 superinfection on pathogenesis and attempts to create a broadly protective prophylactic HIV-1 vaccine is complicated by our inability to quantify the true incidence and prevalence.

Hematopoietic abnormalities including anemia, cytopenias, and alterations of the stem cell plasticity in the bone marrow microenvironment commonly occur in HIV infected patients. These observations suggest that HIV-1 infection may affect processes important during early stages of hematopoiesis or stem cell differentiation. Hematopoietic abnormalities may be caused by altered stem cell differentiation possibly due to abnormal lineage specific expression of certain cellular genes such as cytokines relevant to hematopoiesis. These cytokines could affect regulatory signals important in hematopoiesis. However, in HIV infected individuals, it is not only the virus but also the highly active antiretroviral therapy (HAART) that both contribute to persistent hematopoietic suppression and ensuing cytopenias. Even if a lowering of HIV replication by HAART were to occur in infected individuals, prolonged HAART by itself and / or appearance of drug resistant mutants can contribute to hematopoietic suppression and resulting cytopenias. However, confounding factors such as opportunistic infections, immune mediated effects, or the consequences of prolonged physiological stress, which could contribute to decreased hematopoiesis in patients or other individuals, make the causative role of HIV in vivo, uncertain. The severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues (SCID-hu) is a small animal model which mimics HIV infection in humans, and is useful to determine the mechanisms of HIV-1 induced hematopoietic inhibition and development of drug therapies for interventions of stem cell differentiation. Further, SCID mouse serves as a useful small animal recipient of human progenitor cells and also allows us to study the differentiation of these cells in vivo. Results from our studies are expected to provide relief for HIV infected individuals from hematopoietic inhibition and ensuing cytopenias.

Resistance to antiretroviral drugs is associated with reduced treatment options and, therefore, increased risk of disease progression or death. Despite the main goal of antiretroviral therapy should be achievement of complete suppression of HIV replication, the accumulation of resistance mutations in patients with multiple treatment failure makes this objective often difficult, or even impossible to obtain. Thus, clinicians should be aware about the complex relationship between drug pressure and viral replication capacity and about some potential advantages related to antiretroviral drug resistance. The two main biological mechanisms that can be at the origin of these clinical benefits are: reduction of viral fitness and viral hypersusceptibility. The term “fitness indicates the ability of HIV to maintain high rate of replication capacity in presence of antiretroviral drugs. Consequently, replication capacity, high in presence of wild type virus, tends to decrease when HIV must adapt its enzymes to work in presence of drugs. A reduction of viral fitness is observed in patients harbouring mutations conferring resistance to all the three classes of antiretroviral drugs currently in use. Particularly, the effects on reduction of replication capacity related to M184V mutation in reverse transcriptase are analyzed. Viral isolates with reduced susceptibility or resistance to some antiretroviral drugs may exhibit significant increased susceptibility to other drugs acting on the same enzyme. This phenomenon is known as hypersusceptibility and can be demonstrated in vitro by phenotypic assays. Phenotypic hypersusceptibility has been demonstrated for all three drug classes. Particularly, NNRTI hypersusceptibility, associated with NRTI mutations, is analyzed and discussed.