Snapshot of HIV pathogenesis in China

INTRODUCTION A recent report by the National Intelligence Council es- timates that by 2010 five countries, India, China, Nigeria, Ethiopia and Russia, cumulatively, will harbor the largest number of individuals infected with the Human Immuno- deficiency V…     

Snapshot of HIV pathogenesis in China

Several reviews have focused on the nature of HIV infection and its spread in various geographical regions of China.In contrast, this review provides a comprehensive update on the prevalence of multiple HIV-1 subtypes, consequent emergence of recombinant and novel forms of HIV-1 in China, and the implications this may have on HIV diversity and the development of effective vaccines. In addition it also examines the dissemination of primary drug resistance in therapy na(i)ve patients, as well as co-infections with two other important viruses-hepatitis B and C. The main purpose of this review is to provide a current snapshot of HIV-1 pathogenesis in China and possibly shed some light on the future of HIV evolution, and potential challenges for future vaccine and anti-retroviral therapeutics against HIV strains in this area.     

Snapshot of HIV pathogenesis in China

Several reviews have focused on the nature of HIV infection and its spread in various geographical regions of China. In contrast, this review provides a comprehensive update on the prevalence of multiple HIV-1 subtypes, consequent emergence of recombinant and novel forms of HIV-1 in China, and the implications this may have on HIV diversity and the development of effective vaccines. In addition it also examines the dissemination of primary drug resistance in therapy na?ve patients, as well as co-infections with two other important viruses-hepatitis B and C. The main purpose of this review is to provide a current snapshot of HIV-1 pathogenesis in China and possibly shed some light on the future of HIV evolution, and potential challenges for future vaccine and anti-retroviral therapeutics against HIV strains in this area.     

A hard way to the nucleus

As a member of the Retrovirus family, human immunodeficiency virus (HIV), a causative agent of AIDS, replicates by integrating its genome into the host cell's nuclear DNA. However, in contrast to most retroviruses that depend on mitotic dissolution of the nuclear envelope to gain access to the host cell's genome, the HIV pre-integration complex can enter the nucleus of the target cell during the interphase. Such capacity greatly enhances HIV replication and allows the virus to productively infect terminally differentiated nonproliferating cells, such as macrophages. Infection of macrophages is a critical factor in the pathogenesis of diseases caused by HIV-1 and other lentiviruses. The mechanisms responsible for this unusual feature of HIV have enticed researchers since the early 90s, when the first characterization of the HIV-1 pre-integration complex was reported. Several viral factors, including matrix protein, integrase, viral protein R, and central DNA flap, have been proposed as regulators of HIV-1 nuclear import, only to be later shown as nonessential for this process. As a result, after more than a decade of intense research, there is still no consensus on which HIV-1 and cellular proteins control this critical step in HIV-1 replication. In this review, we will discuss recent advances and suggest possible solutions to the controversial issue of HIV-1 nuclear import.     

HIV-1 Diversity,Drug-Resistant Mutations,and Viral Evolution among High-Risk Individuals in Phase II HIV Vaccine Trial Sites in Southern China

HIV-1 prevalence in Guangxi, China, has been growing since 1996, when the first case was reported. Over half of HIV-1 positive patients in Guangxi Province were injecting drug users (IDUs), possibly because of the province’s location near drug-trafficking routes. Since a phase II HIV vaccine trial is ongoing there, a current characterization of the subtypes of HIV-1 among IDUs in Guangxi would provide critical information for future HIV vaccine trials, as well as further control and prevention of HIV-1 transmission. Thus, we conducted a molecular epidemiological investigation of HIV-1 samples from 2008–2010 among IDUs in multiple cities in Guangxi Province. Our results, based on the gag/pol fragment, indicated a very high proportion (78.47%) of HIV-1 CRF08_BC recombinants, some CRF01_AE (15.38%) recombinants, and a low proportion of CRF07_BC (6.15%) recombinants among the IDUs. The high proportion of CRF08 HIV-1 strains among recent IDUs matches the vaccine candidate constructs. However, future vaccine development should also incorporate CRF01-targeted vaccine candidates. Distinct Env sequence evolution patterns were observed for CRF08_BC and CRF01_AE, indicating that different local selection pressures have been exerted on these two HIV-1 subtypes. Unique drug-resistant mutations were also detected, and our data indicate that HIV treatment programs should consider pre-existing drug-resistant mutations.     

Betulinic acid derivatives as HIV-1 antivirals

Betulinic acid (BA) derivatives are low molecular weight organic compounds synthesized from a plant-derived natural product. Several BA derivatives are potent and highly selective inhibitors of HIV-1. Depending on the specific side-chain modification, these compounds function by inhibiting HIV fusion or, as recently demonstrated, by interfering with a specific step in HIV-1 maturation. BA derivatives have potential as novel HIV-1 therapies, and additional studies of their mechanisms of action are likely to further define the novel targets of these compounds and elucidate the basic biology of HIV-1 fusion and maturation. In this review, recent studies of the novel mechanisms of action of this interesting class of antiviral compounds are discussed.     

Nonstructural HIV proteins as targets for prophylactic or therapeutic vaccines

By the end of 2004, more than 20 HIV-1 vaccine candidates will have entered clinical testing in at least 30 trials worldwide. Almost half of these vaccines include nonstructural HIV-1 gene products. This represents an important innovation in the HIV vaccine field, because until 9 years ago not even preclinical testing in small animal models had been carried out with such immunogens. This review briefly discusses the experimental evidence that provides the rationale for the use of nonstructural HIV-1 gene products as vaccine antigens, and summarizes the current status and the future development of these novel vaccines.     

Mechanisms of the Blood–Brain Barrier Disruption in HIV-1 Infection

Summary 1. Alterations of brain microvasculature and the disruption of the blood–brain barrier (BBB) integrity are commonly associated with human immunodeficiency virus type 1 (HIV-1) infection. These changes are most frequently found in human immunodeficiency virus-related encephalitis (HIVE) and in human immunodeficiency virus-associated dementia (HAD).2. It has been hypothesized that the disruption of the BBB occurs early in the course of HIV-1 infection and can be responsible for HIV-1 entry into the CNS.3. The current review discusses the mechanisms of injury to brain endothelial cells and alterations of the BBB integrity in HIV-infection with focus on the vascular effects of HIV Tat protein. In addition, this review describes the mechanisms of the BBB disruption due to HIV-1 or Tat protein interaction with selected risk factors for HIV infection, such as substance abuse and aging.This revised article was published online in May 2005 with a February 2005 cover date.     

Caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors

HIV-1 integrase (IN) is an essential enzyme for retroviral replication and a rational target for the design of anti-AIDS drugs. In the present study, we have designed, synthesized and tested a series of caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors. Among these compounds, we found that HIV integrase inhibitory activities of compounds III-3 and III-4 were more potent than L-chicoric acid (IC(50)=11.8 microg/mL) and others were comparable to L-chicoric acid. Furthermore, the structure-activity relationships of these compounds were studied. The information gathered from this paper will be useful in the development and design of HIV-1 integrase inhibitors in the future.     

Aspects of gastrointestinal immunology and nutrition in human immunodeficiency virus-1 infection in Brazil

Mucosal surfaces have a fundamental participation in many aspects of the human immunodeficiency virus (HIV) infection pathogenesis. In Brazilian HIV-1 infected subjects, loss of weight and appetite are among the most debilitating symptoms. In this review we describe a defined mucosal immunogen that has profound but transient effects on HIV viral load, and we suggest that gut associated lymphoid tissue under constant immunostimulation is likely to provide a major contribution to the total levels of HIV. We also show that hypermetabolism appears to play a role in the wasting process in Brazilian patients coinfected with HIV and tuberculosis.     

Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism

The destruction of CD4(+) T cells and eventual induction of immunodeficiency is a hallmark of the human immunodeficiency virus type 1 infection (HIV-1). However, the mechanism of this destruction remains unresolved. Several auxiliary proteins have been proposed to play a role in this aspect of HIV pathogenesis including a 14 kDa protein named viral protein R (Vpr). Vpr has been implicated in the regulation of various cellular functions including apoptosis, cell cycle arrest, differentiation, and immune suppression. However, the mechanism(s) involved in Vpr-mediated apoptosis remains unresolved, and several proposed mechanisms for these effects are under investigation. In this review, we discuss the possibility that some of these proposed pathways might converge to modulate Vpr's behavior. Further, we also discuss caveats and future directions for investigation of the interesting biology of this HIV accessory gene.     

Epidemiology and the emergence of human immunodeficiency virus and acquired immune deficiency syndrome

Although acquired immune deficiency syndrome (AIDS) was first described in the USA in 1981, there is evidence that individual cases occurred considerably earlier in Central Africa, and serological and virological data show human immunodeficiency virus (HIV) was present in the Democratic Republic of Congo (DRC) as far back as 1959. It is likely that HIV-1 infection in humans was established from cross-species transmission of simian immunodeficiency virus of chimpanzees, but the circumstances surrounding this zoonotic transfer are uncertain. This presentation will review how causality is established in epidemiology, and review the evidence (a putative ecological association) surrounding the hypothesis that early HIV-1 infections were associated with trials of oral polio vaccine (OPV) in the DRC. From an epidemiological standpoint, the OPV hypothesis is not supported by data and the ecological association proposed between OPV use and early HIV/AIDS cases is unconvincing. It is likely that Africa will continue to dominate global HIV and AIDS epidemiology in the near to medium-term future, and that the epidemic will evolve over many decades unless a preventive vaccine becomes widely available.     

Genetic basis of HIV-1 resistance and susceptibility: an approach to understand correlation between human genes and HIV-1 infection

HIV infection is the serious medical and public health issue of present generation. By 2005, it has already infected a cumulative total of more than sixty million people worldwide and the number of HIV positive cases are rising day by day. India is currently estimated to have about 5.1 million infected persons with HIV-1 or AIDS (second only to South Africa) and this number could increase to 24 million in the next ten years. This pandemic situation of the AIDS stimulated a plethora of longitudinal cohort studies which are designed to document medical heterogeneity as well as to mitigate the factors that regulate the HIV-1 infection, disease progression and the immune defenses. In recent years these genetic studies have led to the discovery of various MHC and non MHC encoded genes, which directly or indirectly influence the susceptibility and resistance to HIV infection and AIDS. These genes and their mutated forms and their products which play a major role in determining the susceptibility or resistance to HIV-1 infection and AIDS. These genes have been categorized into MHC or non MHC encoded genes. The MHC encoded genes which determine HIV resistance or susceptibility are HLA-B57, HLA-B58, HLA-B27, HLA-Bw4 and HLA-A11 in Southeast Asians. On the other hand, non MHC encoded genes are CCR5, CCR2, RANTES, CXCL12, CXCR6, CCL3L1, Interleukin-10 (IL-10), and interferon gamma. The site specific mutations in these genes determine the susceptibility or resistance to HIV-1 infection and AIDS. In future the study of host genes in relation to HIV-1 infection may provide the researchers to develop newer chemotherapeutic approaches to prevent or cure HIV-1 infection effectively.     

"Unconventional" Neutralizing Activity of Antibodies Against HIV

Neutralizing antibodies are recognized to be one of the essential elements of the adaptive immune response that must be induced by an effective vaccine against HIV. However, only a limited number of antibodies have been identified to neutralize a broad range of primary isolates of HIV-1 and attempts to induce such antibodies by immunization were unsuccessful. The difficulties to generate such antibodies are mainly due to intrinsic properties of HIV-1 envelope spikes, such as high sequence diversity, heavy glycosylation, and inducible and transient nature of certain epitopes. In vitro neutralizing antibodies are identified using "conventional" neutralization assay which uses phytohemagglutinin (PHA)-stimulated human PBMCs as target cells. Thus, in essence the assay evaluates HIV-1 replication in CD4+ T cells. Recently, several laboratories including us demonstrated that some monoclonal antibodies and HIV-1-specific polyclonal IgG purified from patient sera, although they do not have neutralizing activity when tested by the "conventional" neutralization assay, do exhibit potent and broad neutralizing activity in "unconventional" ways. The neutralizing activity of these antibodies and IgG fractions is acquired through post-translational modifications, through opsonization of virus particles into macrophages and immature dendritic cells (iDCs), or through expression of antibodies on the surface of HIV-1-susceptible cells. This review will focus on recent findings of this area and point out their potential applications in the development of preventive strategies against HIV.     

＂Unconventional＂ Neutralizing Activity of Antibodies Against HIV

Neutralizing antibodies are recognized to be one of the essential elements of the adaptive immune response that must be induced by an effective vaccine against HIV. However,only a limited number of antibodies have been identified to neutralize a broad range of primary isolates of HIV-1 and attempts to induce such antibodies by immunization were unsuccessful. The difficulties to generate such antibodies are mainly due to intrinsic properties of HIV-1 envelope spikes,such as high sequence diversity,heavy glycosylation,and inducible and transient nature of certain epitopes. In vitro neutralizing antibodies are identified using "conventional" neutralization assay which uses phytohe-magglutinin (PHA)-stimulated human PBMCs as target cells. Thus,in essence the assay evaluates HIV-1 replication in CD4 T cells. Recently,several laboratories including us demonstrated that some monoclonal antibodies and HIV-1-specific polyclonal IgG purified from patient sera,although they do not have neutralizing activity when tested by the "conventional" neutralization assay,do exhibit potent and broad neutralizing activity in "unconventional" ways. The neutralizing activity of these antibodies and IgG fractions is acquired through post-translational modifications,through opsonization of virus particles into macrophages and immature dendritic cells (iDCs),or through expression of antibodies on the surface of HIV-1-susceptible cells. This review will focus on recent findings of this area and point out their potential applications in the development of preventive strategies against HIV.     

HIV病毒潜伏库的形成机制和对策挑战

长期以来,病毒潜伏库(latent viral reservoir, LVR)的存在严重阻碍了AIDS的有效治疗,LVR无法被人体免疫系统识别,高效抗逆转录病毒疗法(highly active antiretroviral therapy, HAART)对其无效,一旦中断抗病毒治疗,患者会出现快速耐药和病毒血症反弹。截至目前,研究报道的克服该障碍最常用的方案是"激活并杀死"策略,即应用潜伏库逆转剂(latency-reversing agents, LRAs)重新激活潜伏的HIV-1病毒,再利用抗病毒药物和人体免疫系统杀死激活的病毒;另一种方法是通过不可逆地抑制HIV-1的转录使病毒永久沉默,不再具有转录活化的能力。本文综述了HIV-1 LVR的形成和维持机制以及目前文献中报道的LRAs,并介绍了一种使病毒永久沉默的基因疗法,旨在为HIV-1感染提供更安全有效的治疗方法。     

Molecular epidemiological analysis of the spread of human immunodeficiency virus (HIV) infection in the Novosibirsk region

The dynamics of the spread of individual subtypes of type 1 HIV (HIV-1), circulating in the Novosibirsk region during the epidemic rise of HIV infection was under study. The epidemic of HIV-1 in Novosibirsk has a pattern similar to that in Russia as a whole. At the initial stage of epidemics multiple sources of virus determine the heterogeneity of the isolated subtypes of HIV-1. Then the parenteral route of HIV transmission, connected with the intravenous use of narcotic drugs, becomes dominant. Recently the spread of HIV-1 from the group of intravenous drug users to other groups of the population has been observed. In the circulation of HIV-1 among drug users the leading role was shown to belong to subtype A, which ensures its rapid spread and dominating role in the epidemic process. Further spread of the HIV-1 epidemic is expected to proceed in parallel to the spread of viral hepatitis, sexually transmitted diseases and drug addiction. Thus, HIV-1, subtype A, may be assumed to be dominant in the Novosibirsk region in the nearest future.