Current HIV Research - Volume 2, Issue 4, 2004

Immunization is an important measure to protect HIV-infected children and adults against certain vaccine preventable diseases. However, the antibody response, which is associated with the level of CD4+ T cell count, is frequently impaired in this group of patients. Certain vaccines enhance virus replication and transiently increase HIV viral load. Theoretically, vaccination should be given before the immune status of the patients is suppressed. Inactivated vaccines are generally safe and are beneficial for HIV-infected patients. These vaccines should be administered at appropriate age recommended for immunocompetent individuals. Live vaccines should be used with caution since some of the vaccines may be harmful to patients with severe immunologic suppression. Recommendations for immunization in HIV-infected patients may differ from country to country, depending on the availability and affordability of each vaccine, and the prevalence of each preventable disease. Vaccine trial in HIV-infected patients is needed in order to establish the most appropriate vaccine recommendation for this group of patients.

In a previous work, we have showed in mice infected with an avirulent strain of Toxoplasma gondii and receiving a didanosine treatment, an important decrease of brain cysts. It is why, the purpose of this study was to investigate the effect of didanosine treatment on AIDS patients having developed Toxoplasma encephalitis. 60 patient reports were analyzed: 22 patients (group 1) did not received didanosine in their antiretroviral treatment and 38 (group 2) were treated with didanosine. The results showed that an antiretroviral therapy was prescribed for 93 % of patients, 50 % of them received only zidovudine and protease inhibitors were prescribed for 37 %. The regimens given most frequently were those including zidovudine plus lamivudine or zidovudine plus indinavir. Among the group 1, 18 % have had a relapse of Toxoplasma encephalitis. In the group 2, 37 % of the patients suffered from one episode of TE while 16 % have had two TE after the pause in their didanosine treatment, the maximum occurring between 4 and 24 months after the pause of didanosine. This study showed that didanosine seems to have an effect on cerebral cysts. Also, this work made a synthesis about the different treatment used in AIDS patients and the new molecules yet in development against T. gondii.

Due to genetic and environmental factors, there are wide inter-patient differences when measuring drug exposure to a standard dose. If there is a relationship between drug exposure and efficacy or toxicity, this inter-patient variability carries various risks to develop toxicity or failure. Therapeutic drug monitoring is an attempt to adjust the dose to obtain a level within a therapeutic range consisting in a minimum plasma concentration needed to be efficacious and a maximum plasma concentration not to exceed to avoid toxicity. Many studies have shown a relationship between various pharmacokinetic parameters and drug toxicity or efficacy for HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Therapeutic drug monitoring (TDM) proves to be a useful tool to assess adherence, to investigate drug-drug interactions between antiretroviral (ARV) drugs or with co-medications, to prevent some ARV drug toxicities, to adjust the dosage in particular populations, and to increase ARV efficacy of some drugs in naive patients. The integration of virological and pharmacological parameters, using inhibitory quotients, looks promising to improve therapy in ARV-experienced patients. Effective and non-toxic target concentrations will be determined for all present and future antiretroviral drugs covering the extended spectrum of naive patients to multiple failures. In this article, we review the rationale of TDM for antiretroviral drugs, the retrospective and prospective studies assessing plasma drug concentrations in relation with antiretroviral toxicity or efficacy, and the actually recommended or proposed indications for TDM. We also highlight the benefits and limits of this tool as an adjunct in the care of HIV-infected patients.

Nonnucleoside reverse transcriptase inhibitors (NNRTI) are a group of small hydrophobic compounds with diverse structures that specifically inhibit HIV-1 reverse transcriptase (RT). NNRTIs interact with HIV-1 RT by binding to a single site on the p66 subunit of the p66 / p51 heterodimeric enzyme, termed the NNRTI-binding pocket (NNRTI-BP). This binding interaction results in both short-range and long-range distortions of RT structure. In this article, we review the structural, computational and experimental evidence of the NNRTI-induced conformational changes in HIV-1 RT and relate them to the mechanism by which these compounds inhibit HIV-1 reverse transcription.

Cytokines are small proteins produced by T lymphocytes that mediate immune responses. Those produced by the CD4+ Th1 subset induce cell-mediated immunity, whereas those produced by the CD4+ Th2 subset are more efficient at stimulating immunoglobulin production. The goal of cytokine immunotherapy is prevention or reduction of disease progression through stimulation of cell-mediated immunity (i.e., immune reconstitution) by administration of an exogenous Th1 cytokine such as interleukin-2 (IL-2). Cytokine immunotherapy has its origins in cancer immunobiology where IL-2 has been used successfully to manage several human cancers (metastatic melanoma, acute myelogenous leukemia, and metastatic renal cell carcinoma). More recent work has demonstrated cytokine immunotherapy to be effective at improving immune responses in patients with HIV-1 disease. To explore cytokine immunotherapy for sight-threatening AIDSrelated human cytomegalovirus (HCMV) retinitis, we developed a mouse model of experimental murine cytomegalovirus (MCMV) retinitis that employs mice with MAIDS, a retrovirus-induced immunodeficiency syndrome. Systemic cytokine immunotherapy with IL-2, but not with interleukin-12 (IL-12), provides absolute protection against MAIDS-related MCMV retinitis by stimulation of the perforin-mediated pathway of cytotoxicity used by natural killer cells and cytotoxic CD8+ T cells to kill virus-infected cells. Our findings warrant additional studies on the use of cytokine immunotherapy for management of HCMV retinitis (and possibly other opportunistic infections) during HIV-1-induced immunodeficiency. We envision systemic cytokine immunotherapy as an altemative or adjunct to traditional antiviral chemotherapy for optimal management of AIDS-related HCMV retinitis.

HIV-1 infection predisposes to the development of specific types of cancer. Most cancers seen in the AIDS setting are related to oncogenic virus infections, such as Epstein-Barr virus (EBV), Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) and human papillomavirus (HPV). It is generally assumed that HIV-1 infection play a passive role in cancer development by impairing the host immune surveillance and increasing the risk of oncogenic virus infection. Recent insights, however, indicate that HIV-1 infection more actively promotes cancer growth. Experimental evidence has shown that HIV-1-encoded proteins can directly induce tumor angiogenesis and enhance KSHV transmission to target cells. Clinical evidence suggests that the oncogenicity of HPV is altered by the presence of HIV-1 infection irrespective of host immune status. The introduction of highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of KS whereas the impact of HAART is variable in EBV-related lymphoma and HPV-related cervical cancer, suggesting that additional factors are involved in the pathogenesis of these cancers. Understanding the direct and indirect roles of HIV-1 in the pathogenesis of neoplastic conditions could provide the rationale for prevention and development of new treatments for AIDS-associated malignancies.

While detrimental consequences of biological interaction between HIV and M. tuberculosis are well described, immune mechanisms underlying the evolution of HIV and mycobacterial coinfection remain poorly characterized. Recent studies in HIV-infected humans and SIV-infected monkeys have enhanced our understanding of complex issues of HIV and M. tuberculosis coinfection. Importantly, an anti-viral immune response and an associated control of AIDS virus infection can be induced during coinfection with mycobacterium or other pathogens in HIV-infected humans or SIV-infected monkeys. Restoration of antimycobacterial immunity during antiretroviral treatment can contribute to prevention and treatment of AIDSrelated mycobacterial diseases. This article discusses recent progress in immune aspects of HIV and mycobacterial coinfection.

Over the last two decades most of the efforts in HIV vaccine development have been based on the use of the HIV Env with the goal to induce sterilizing immunity. However, as a result of Env variability disappointing results have been obtained in preclinical and phase III clinical trials. Although the objective of a preventive immunity still remains a priority, secondary endpoints (e.g. block of virus replication and disease onset) are being considered at the present as more achievable end-points in HIV vaccine development. This is based on accumulating evidence indicating that low viral load correlates with maintenance of immune functions and slow progression to disease, and that cell-mediated immunity plays a major protective role in the absence of sterilizing immunity. The promising results obtained in non-human primates with a vaccine based on a native Tat protein (B-clade), which is an early regulatory protein key for HIV replication and AIDS pathogenesis, highlights the importance of targeting the virus very early after infection. In particular, the immune response against Tat appears to modify the virus-host interactions at the very beginning of infection, thus containing the depletion of critical immune cells and the progression of infection. Moreover, since Tat targets and induces maturation of dendritic cells, has immunomodulatory activities and drives Th-1 and CTL responses, immunization with Tat may drive or increase these immune responses also against other HIV antigens to support an effective, long-lasting and hopefully even sterilizing antiviral immunity. Finally, Tat B-clade is similarly recognized by sera from individuals infected by different virus clades (A, B, C, D) supporting the concept of a cross-clade vaccine. Therefore, the Tat-vaccine should contain virus replication protecting from disease progression (non-sterilizing immunity) or even favoring an abortive infection. Although only a phase III clinical trial will establish the efficacy of this vaccine strategy, the Tat-vaccine has recently entered preventive and therapeutic phase I clinical testing in Italy to establish safety (primary-endpoint) and immunogenicity (secondary end-point) and phase II studies are being prepared.

Response to HIV / AIDS epidemic in resource-constrained countries is still woefully disappointing. This paper highlights some priorities shared at recent Florence World Conference (Florence, Italy: January 21st-24th, 2004) on how to overcome the obstacles still delaying sustainable fight against HIV / AIDS in developing world areas. Messages reported here result from selection made by the authors among challenging topics by more than one hundred speakers and have been chosen because of their value as most practical ways to secure prevention, treatment and care and achieve self-managing in fighting epidemic in income-limited settings. Building for success means to set up combined strategies - actively involving people living with HIV / AIDS (PLWHA) and grounded on coordination, coalition and partnership among all players - to prevent HIV transmission at mother-to-child, young and adult levels and to improve availability and access to laboratory testing and monitoring as well as to essential drugs for HIV / AIDS and related diseases. Building for success also means to provide women with reliable and affordable vaginal microbicides and to look for control of coinfections such as viral hepatitis, intestinal and sexually transmitted diseases as well as tuberculosis and malaria. Among the measures taken into account, the need for education and training is emphasised because its value may be even more important than funding in some countries. Priorities suggested in this paper reinforce each other underscoring the bidirectional value and synergy of the treatment and prevention strategies together with the need for keeping prevention in people giving successful antiretroviral treatment. In the Author's opinion, the current HIV / AIDS scenario may be reversed if the priorities taken into account will entirely be applied through adaptation to the different cultural backgrounds and social settings, and based on achievement of government's political will and accountability as well as on properly coordinated technical, financial and human support from international health cooperation.

Much attention has been focused on CD4+ memory / primed T cells and monocytes / macrophages as the predominant targets of HIV infection. Considerable evidence, however, indicates that cell types that are classically not permissive to HIV infection, can be a potent source of productive virus replication in response to immune modulation. This immune modulation can be in the form of cytokine stimulation pre- or postinfection or by activating these “non-conventional” targets. In this review, we will provide evidence for immune modulation of HIV infection with special emphasis on immune modulation of HIV replication in classically non-HIV permissive primary cells of both lymphoid and non-lymphoid origins. We will also examine the impact of HIV infection of these non-conventional targets as they pertain to both HIV immunoand neuro-pathogenesis.