The rationale and development of new drugs to treat HIV infection

Fewer than one million HIV infected individuals are currently receiving antiretroviral therapy. Present antiretroviral therapy costs between 10,000 dollars and 20,000 dollars per year, which provides excellent value for money in developed countries with a cost of about 10,000 dollars per life year saved; this compares very favourably with other therapies in chronic use. Recent studies have demonstrated a dramatic decline in HIV and AIDS related morbidity and mortality across developed countries and these reductions have been sustained since the introduction of highly active antiretroviral therapy (HAART) since 1996. The use of HAART has been associated with specific toxicities related to the drug class, problems with adherence with the subsequent emergence of viral isolates and resistance associated mutations. The replacement of older therapies with newer drugs that avoid cross resistance even within the same class of antiretroviral, represents a new hope in retroviral targeting.     

HIV infection: first battle decides the war

The traditional view of HIV-1 infection characterized by the slow decline of CD4+ T cells has radically changed in light of recent observations in rhesus macaques and humans of rapid and extensive infection and removal of memory CD4+ T cells in mucosal tissues within the first three weeks of infection. This initial strike to the immune system seems to be the distinguishing feature of HIV-1 pathogenesis and its extent sets the overall course of the ensuing infection. Qualitatively different mechanisms of CD4+ T-cell depletion prevail during the acute, chronic and advanced phases of infection depending on the availability of the target-cell population and competence of the immune system. The elimination of CD4+ T cells in mucosal lymphoid tissues results in the absence of important regulatory and effector functions that these cells normally perform in controlling immune responses to environmental antigens and pathogens. Ablation of acute HIV-1 viremia limits the initial damage to the CD4+ T-cell compartment and helps to establish a state of equilibrium between the replicating virus, the availability of the target-cell population and the immune control characteristic of long-term non-progression.     

Opportunities to diagnose, treat, and prevent HIV in the criminal justice system

Persons involved with the criminal justice system are at risk for HIV and other transmissible diseases due to substance use and related risk behaviors. Incarceration provides a public health opportunity to test for HIV, viral hepatitis, and other sexually transmitted infections, provide treatment such as highly active antiretroviral therapy, and link infected persons to longitudinal comprehensive HIV care upon their release for such comorbidities as addiction and mental illness. Delivering health interventions inside prisons and jails can be challenging, yet the challenges pale in comparison to the benefits of interventions for inmates and their communities. This article reviews the current state of delivering HIV testing, prevention, treatment, and transition services to incarcerated populations in the United States. It concludes with summary recommendations for research and practice to improve the health of inmates and their communities.     

Vaccination to treat persistent viral infection

Persistent infections caused by such agents as the human immunodeficiency virus, hepatitis B virus, Epstein-Barr virus, etc., present formidable medical problems. A defining characteristic of these infections is that anti-viral cytotoxic T lymphocytes (CTL) may be lost or, if present, fail to clear the infection. Here we report a vaccination strategy which was successful in generating lytic CTL in persistently infected mice. Vaccination with an immunodominant CTL epitope derived from the nucleoprotein of lymphocytic choriomeningitis virus (LCMV) delivered in the form of a lipopeptide incorporating a universal CD4 helper epitope successfully induced lytic MHC-restricted CTL in mice persistently infected with LCMV since birth. However, induction of such CTL did not eliminate the virus, most likely because the CTL were generated at low frequencies and had 2 to 3 logs lower affinity than CTL generated in uninfected mice inoculated with the vaccine. Both CTL populations from either uninfected or persistently infected mice produced significant and similar amounts of interferon-gamma and IL-6. Vaccine-induced low-affinity CTL were still inadequate at complete removal of the virus when combined with LCMV-specific CD4 helper T lymphocytes. Thus, our results establish that CTL can be generated in persistently infected mice and that a crucial factor for clearing viral infection is the affinity of the CTL.     

Attachment and fusion inhibitors potently prevent dendritic cell-driven HIV infection

Dendritic cells (DCs) efficiently transfer captured (trans) or de novo-produced (cis) virus to CD4 T cells. Using monocyte-derived DCs, we evaluated entry inhibitors targeting HIV envelope (BMS-C, T-1249) or CCR5 (CMPD167) for their potency to prevent DC infection, DC-driven infection in T cells in trans and cis, and direct infection of DC-T-cell mixtures. Immature DC-T-cell cultures with distinct mechanisms of viral transfer yielded similar levels of infection and produced more proviral DNA compared with matched mature DC-T-cell cultures or infected immature DCs. Although all compounds completely blocked HIV replication, 16 times more of each inhibitor (250 vs 15.6 nM) was required to prevent low-level infection of DCs compared with the productive DC-T-cell cocultures. Across all cell systems tested, BMS-C blocked infection most potently. BMS-C was significantly more effective than CMPD167 at preventing DC infection. In fact, low doses of CMPD167 significantly enhanced DC infection. Elevated levels of CCL4 were observed when immature DCs were cultured with CMPD167. Viral entry inhibitors did not interfere with Candida albicans-specific DC cytokine/chemokine responses. These findings indicate that an envelope-binding small molecule is a promising tool for topical microbicide design to prevent the infection of early targets needed to establish and disseminate HIV infection.     

Switching from a Toxicity-Causing Antiretroviral to Enfuvirtide in Patients with HIV: The SWITCH TOX Study

Abstract

Purpose: Treatment-related toxicities frequently limit antiretroviral therapy for patients with HIV-1 infection. This study evaluated the changes in treatment-limiting toxicities when the primary toxicity-causing agent was replaced with enfuvirtide. Method: Adult patients with HIV-1 infection (N = 91) with antiretroviral treatment-limiting toxicities were enrolled in this multicenter, open-label, single-arm, 24-week study. Enfuvirtide 90 mg bid was administered instead of a single toxicity-causing component of the previous antiretroviral regimen. Changes in severity of antiretroviral toxicity, safety, tolerability, and maintenance of efficacy of the enfuvirtide regimen were evaluated at baseline and at 4, 8, 12, and 24 weeks. Results: Eighty-four percent of participants completed the study. Injection site reactions with enfuvirtide caused premature withdrawal in 5 participants (5%); a further 10 participants (11%) also withdrew early. Overall antiretroviral-related, treatment-limiting toxicities improved or resolved in 53% of participants switching to enfuvirtide, remained unchanged in 43%, and worsened in 3%. At Week 24, 66% of participants (60/91; intent-to-treat population) maintained or improved their viral load category and 73% of participants (66/91) maintained or improved their CD4 cell counts. Conclusion: Replacing a toxicity-causing antiretroviral with enfuvirtide may reduce toxicity without compromising the efficacy of different antiretroviral regimens.     

Evaluation of simplified protease inhibitor dosing regimens for the treatment of HIV infection

Complicated dosing regimens can unfavorably affect patient adherence and drug efficacy. In an effort to increase adherence while maximizing the benefits of the protease inhibitor (PI) component of HAART, the efficacy and safety of less frequent PI dosing regimens have recently been under scrutiny. Limiting the number of drugs required in antiretroviral therapy regimens may also minimize toxicity and drug-drug interactions. This article reviews the current movement toward twice-daily regimens and examines the efficacy and safety data available on twice-daily dosing of amprenavir, indinavir, nelfinavir, saquinavir soft-gel capsules, and ritonavir. Future trends in dosing are also discussed.     

It is hazardous to treat HIV patients with interferon-alpha

Interferon-alpha is shown to play a key role in the progressing immunodysfunction that characterizes HIV infection. In particular, interferon-alpha is responsible for the development of an autoimmune state that is prone to serious complications. Therefore, treatment of HIV patients with IFN-alpha is hazardous. There are results suggesting that anti-interferon-alpha immunization might be a method for prophylaxis and treatment of the autoimmune state in HIV patients. This treatment may prevent complications of HIV infection and the transition to AIDS.     

Disease progression, adherence, and response to protease inhibitor therapy for HIV infection in an Urban Veterans Affairs Medical Center

Indinavir therapy has demonstrated promise in the treatment of HIV-1 infection in clinical trials; however, its efficacy in a U.S. Veterans Affairs Medical Center, where access to therapy is generally unimpeded, is unknown. A review of the Miami cohort was conducted for the year beginning May 1996 to evaluate response to indinavir plus two nucleoside analogues. Of 483 HIV-1-positive patients (97% male; mean age, 46.7+/-9.7 years), 266 were offered indinavir based on their having CD4 counts <200 cells/microl or viral loads >10,000 copies/ml. Of these patients, 36% were adherent and experienced significant reductions in viral loads (-93,325+/-147,911 copies/ml) and elevations in CD4+ (111+/-103 cells/microl) and CD8+ (225+/-338 cells/microl) T cell counts. Adherent patients with baseline CD4 counts <100 cells/microl were 4.5 times more likely to have follow-up viral loads >10,000 copies/ml than those with CD4 >200 cells/microl. Adherent patients with CD4 counts <100 cells/microl did not show evidence of immune "exhaustion" because they were equal to those with CD4 counts >200 cells/microl in their capacity to replenish CD4 cells. Nonadherence to the regimen resulted in loss of therapeutic benefit and suggested that strategies to enhance adherence may become an essential component of treatment.     

B-cell responses to HIV infection

The induction of neutralizing antibodies directed against the human immunodeficiency virus (HIV) has received considerable attention in recent years, in part driven by renewed interest and opportunities for antibody-based strategies for prevention such as passive transfer of antibodies and the development of preventive vaccines, as well as immune-based therapeutic interventions. Advances in the ability to screen, isolate, and characterize HIV-specific antibodies have led to the identification of a new generation of potent broadly neutralizing antibodies (bNAbs). The majority of these antibodies have been isolated from B cells of chronically HIV-infected individuals with detectable viremia. In this review, we provide insight into the phenotypic and functional attributes of human B cells, with a focus on HIV-specific memory B cells and plasmablasts/cells that are responsible for sustaining humoral immune responses against HIV. We discuss the abnormalities in B cells that occur in HIV infection both in the peripheral blood and lymphoid tissues, especially in the setting of persisting viremia. Finally, we consider the opportunities and drawbacks of intensively interrogating antibodies isolated from HIV-infected individuals to guide strategies aimed at developing effective antibody-based vaccine and therapeutic interventions for HIV.     

Complexities of targeting innate immunity to treat infection

Innate immunity is an ancient form of host defence that is activated rapidly to enable, through a multiplicity of effector mechanisms, defence against a broad spectrum of microbial threats. From this perspective, innate immunity has desirable characteristics of a therapy against infections, and, as a consequence, the innate immune system has become a major target for the development of therapeutics to control inflammation and immune defences. Although advances in the field have come at a furious pace, and several companies are advancing the first Toll-like receptor-based drugs, there remain many unanswered questions about innate immunity and maintaining balance in the immune response. Indeed, innate immunity represents an enormously complex network of molecules, pathways and interactions, controlled by multiple positive and negative regulatory proteins, which are starting to be evaluated in more depth using systems biology approaches. However, accompanying the protective mechanisms is the production of pro-inflammatory cytokines such that, if excessive amplification of innate immunity occurs, there is the potential for such syndromes as sepsis and chronic inflammation.     

Antiviral activity of a Rac GEF inhibitor characterized with a sensitive HIV/SIV fusion assay

A virus-dependent fusion assay was utilized to examine the activity of a panel of HIV-1, -2, and SIV isolates of distinct coreceptor phenotypes. This assay allowed identification of entry inhibitors, and characterization of an antagonist of a Rac guanine nucleotide exchange factor, as an inhibitor of HIV-mediated fusion.