HIV-1 vaccines and co-infection

Vaccines are an economically efficient means of controlling viral infections, and it is likely that a vaccine against HIV-1 will be the most effective way of controlling the global AIDS crisis. However, an effective vaccine has not yet been attainable and in developing countries co-infection with protozoa and other chronic diseases adds another level of complexity to the design of an HIV-1 vaccine. Helminthic and protozoan infections can result in a constant state of immune activation that is characterised by a dominant T helper (Th)2 type of cytokine profile. Such an immune profile is likely to have an adverse impact on the efficacy of an HIV-1 vaccine CD8 cellular immune response and the corresponding Th1 cytokines that are most likely to be important for clearing viral infections.     

The prozone phenomenon with syphilis and HIV-1 co-infection

The prozone phenomenon in syphilis testing refers to a false negative response resulting from overwhelming antibody titers which interfere with the proper formation of the antigen-antibody lattice network necessary to visualize a positive flocculation test. This prozone effect in syphilis testing can be expected in cases of disproportionately high antibody titers, such as secondary syphilis, or with human immunodeficiency virus (HIV) coinfection. Clinicians need to remain familiar with the protean manifestations of syphilis to be able to exclude the prozone phenomenon.     

HIV-1 vaccines: the search continues

This article gives an overview about the development of an HIV-1 vaccine. Tremendous numbers of papers have been published on this topic during the last 10 years, and this article can only touch on the different directions taken toward the development of an HIV-1 vaccine, and not give a complete overview of the entire field.     

大理市HIV感染者中HCV感染状况的研究

目的探讨人类免疫缺陷病毒(HIV)-1感染者中丙型肝炎病毒(HCV)的混合感染率,并了解HCV对HIV-1感染者CD4+T细胞计数的影响。方法采用横断面研究方法,在云南大理市招募HIV-1感染者,分别采用血清学和核酸方法检测HCV混合感染。结果在526例HIV-1感染者中,静脉吸毒者占94.3%,其余为性途径感染。86.9%(457/526)为HCV血清学检测抗体阳性,其中HCV核酸阳性者占78.3%。在HCV血清学阴性的69例中,24例HCV RNA>1 000 IU/mL。由于引入HCV核酸检测方法,现场HCV混合感染的发现率增加了4.6%(24/526),所调查的HIV-1感染者中HCV混合感染率为91.4%。HCV混合感染者的CD4+T细胞计数明显低于HIV-1单纯感染者。结论在HCV感染的高流行区或髙危人群中,HCV与HIV-1共感染率较高。筛查HIV-1感染时应加强对HCV的检测,有助于对HCV感染进行早期诊断并开展HCV的早期治疗,减少HCV对HIV-1感染者的不利影响。     

Role of therapeutic vaccines in the control of HIV-1

The recent success of highly active antiretroviral therapy (HAART) has altered the prognosis of patients living with HIV-1 infection. However, there are still many challenges to be addressed if we want to develop long-term therapeutic strategies for patients, in both the Western world and resource-poor countries. In this review, the potential role for HIV-1 therapeutic vaccines in the era of HAART will be discussed in the light of the present efforts at developing immune-based therapies to complement antiviral treatment and minimize the duration of exposure to antiviral drugs.     

Conserved immunogens in prime-boost strategies for the next-generation HIV-1 vaccines

Introduction: Effective vaccines are the best solution for stopping the spread of HIV/AIDS and other infectious diseases. Their development and in-depth understanding of pathogen–host interactions rely on technological advances.

Areas covered: Rational vaccine development can be effectively approached by conceptual separation of, on one hand, design of immunogens from improving their presentation to the immune system and, on the other, induction of antibodies from induction of killer CD8⁺ T cells. The biggest roadblock for many vaccines is the pathogens' variability. This is best tackled by focusing both antibodies and T cells on the functionally most conserved regions of proteins common to many variants, including escape mutants. For vectored vaccines, these ‘universal’ subunit immunogens are most efficiently delivered using heterologous prime-boost regimens, which can be further optimised by adjuvantation and route of delivery.

Expert opinion: Development of vaccines against human diseases has many features in common. Acceleration of vaccine discovery depends on basic research and new technologies. Novel strategies should be safely, but rapidly tested in humans. While out-of-the-box thinking is important, vaccine success largely depends on incremental advances best achieved through small, systematic, iterative clinical studies. Failures are inevitable, but the end rewards are huge. The future will be exciting.     

Impact of preexisting vector immunity on the efficacy of adeno-associated virus-based HIV-1 Gag vaccines

Vectors based on primate-derived adeno-associated virus (AAV) are being considered in the development of genetic vaccines against a number of diseases including infection with HIV-1. Preexisting immunity to the vaccine carrier as a result of natural infections could potentially compromise vaccine efficacy. This study evaluates the impact of neutralizing antibodies against AAV capsids on the ability of HIV-1 Gag-expressing vectors to elicit transgene-specific T and B cell responses. Mice were passively transferred with pooled human immunoglobulin at various doses to simulate human antivector humoral immunity. Vectors based on serotype 2, which were evaluated in the clinic, were compared with those created from the novel monkey isolates AAV7 and AAV8. Inhibition of AAV2-directed Gag responses occurred at doses of human immunoglobulin 10- to 20-fold less than was required to inhibit immunogenicity of AAV7 and AAV8 vectors. Cynomolgus macaques were screened for preexisting immunity to AAV7 and AAV8 and sera from individual animals were passively transferred into mice that were analyzed for AAV vaccine efficacy. There was a correlation between the level of preexisting capsid neutralizing titers and diminution of vaccine efficacy; sera from a number of animals with no detectable neutralizing antibodies showed partial vaccine inhibition, suggesting that the in vitro assay is less sensitive than the in vivo passive transfer assay for detecting neutralizing antibodies to AAV.     

Impact of codon usage modification on T cell immunogenicity and longevity of HIV-1 gag-specific DNA vaccines

In this study, we analyzed the in vitro expression, potency and longevity of immune responses induced in a Balb/c mouse model by a synthetic HIV-1 GAG gene exhibiting a codon usage that was adapted to that of highly expressed mammalian genes (syngag). In contrast to a vector containing the wild-type (wt) GAG gene, the syngag construct enabled highly efficient Gag expression in both human and rodent cell lines in complete absence of Rev and Rev-responsive element. Immunization of Balb/c mice with the wt gag plasmid DNA induced only weak and inconsistent humoral immune responses. Mice vaccinated by syngag but not wt gag developed substantial and highly consistent Gag-specific antibody titers showing a clear T helper 1 polarization even with low doses of DNA. Moreover, vaccinated mice developed a strong Gag-specific cellular immune response, including cytotoxic T cells, which was not observed in wt gag-immunized animals. Both humoral and cellular immunity were efficient and lasted for more than 20 weeks. Furthermore, the induction of the humoral as well as the cellular immune response was independent of the immunization route (intramuscular or subcutaneous). These results clearly show the advantages of codon-optimized genes with respect to the expression and immunogenicity of plasmid DNA constructs, making them promising vaccine candidates for further studies.     

Early therapy in HIV-1-infected children: effect on HIV-1 dynamics and HIV-1-specific immune response

BACKGROUND: Perinatal HIV-1 infection is acquired in the milieu of a developing immune system, leading to high levels of uncontrolled viral replication. Few data have been reported that address the viral dynamics and immunological response in infants who initiated aggressive antiretroviral therapy (ART) shortly after birth. METHODS: Six HIV-1-infected infants who started ART within 3 months of age were studied. The median followup was 61 months. Plasma HIV-1 RNA, cell-associated HIV-1 DNA, unspliced and multiply spliced HIV-1 mRNAs, HIV-1 antibodies, and CD4+ and CD8+ T-cell subsets were assessed in sequential peripheral blood samples. HIV-1 cellular immune response was measured by EliSpot assay. RESULTS: All children showed a decline in plasma viraemia to undetectable levels. HIV-1 DNA persisted in four children, but only two of these had detectable HIV-1 mRNA. All viral parameters remained persistently negative in two children. Only two children produced HIV-1 antibodies, while the others, after having lost maternal antibodies, remained seronegative. No HIV-1 cellular immune response was observed in any child. Therapy interruption was performed in two children: one HIV-1-seropositive and one HIV-1-seronegative with persistently undetectable levels of all viral parameters. Rebound of HIV-1 plasma viraemia in the seronegative child was more rapid and higher than that observed in the seropositive child. CONCLUSIONS: Early ART treatment in infants modifies the natural course of infection by controlling HIV-1 replication and reducing viral load to below the threshold levels required for onset of HIV-1 immune response, but does not prevent the establishment of a reservoir of latently infected cells that precludes virus eradication.     

Comparative clonal analysis of human immunodeficiency virus type 1 (HIV- 1)-specific CD4+ and CD8+ cytolytic T lymphocytes isolated from seronegative humans immunized with candidate HIV-1 vaccines

The lysis of infected host cells by virus-specific cytolytic T lymphocytes (CTL) is an important factor in host resistance to viral infection. An optimal vaccine against human immunodeficiency virus type 1 (HIV-1) would elicit virus-specific CTL as well as neutralizing antibodies. The induction by a vaccine of HIV-1-specific CD8+ CTL in humans has not been previously reported. In this study, CTL responses were evaluated in HIV-1-seronegative human volunteers participating in a phase I acquired immune deficiency syndrome (AIDS) vaccine trial involving a novel vaccine regimen. Volunteers received an initial immunization with a live recombinant vaccinia virus vector carrying the HIV-1 env gene and a subsequent boost with purified env protein. An exceptionally strong env-specific CTL response was detected in one of two vaccine recipients, while modest but significant env-specific CTL activity was present in the second vaccinee. Cloning of the responding CTL gave both CD4+ and CD8+ env-specific CTL clones, permitting a detailed comparison of critical functional properties of these two types of CTL. In particular, the potential antiviral effects of these CTL were evaluated in an in vitro system involving HIV-1 infection of cultures of normal autologous CD4+ lymphoblasts. At extremely low effector-to-target ratios, vaccine-induced CD8+ CTL clones lysed productively infected cells present within these cultures. When tested for lytic activity against target cells expressing the HIV-1 env gene, CD8+ CTL were 3-10-fold more active on a per cell basis than CD4+ CTL. However, when tested against autologous CD4+ lymphoblasts acutely infected with HIV-1, CD4+ clones lysed a much higher fraction of the target cell population than did CD8+ CTL. CD4+ CTL were shown to recognize not only the infected cells within these acutely infected cultures but also noninfected CD4+ T cells that had passively taken up gp120 shed from infected cells and/or free virions. These results were confirmed in studies in which CD4+ lymphoblasts were exposed to recombinant gp120 and used as targets for gp120-specific CD4+ and CD8+ CTL clones. gp120-pulsed, noninfected targets were lysed in an antigen-specific fashion by CD4+ but not CD8+ CTL clones. Taken together, these observations demonstrate that in an in vitro HIV-1 infection, sufficient amounts of gp120 antigen are produced and shed by infected cells to enable uptake by cells that are not yet infected, resulting in the lysis of these noninfected cells by gp120-specific, CD4+ CTL.(ABSTRACT TRUNCATED AT 400 WORDS)     

HIV-1 reservoirs

In most infected individuals, HIV-1 replicates high levels throughout the duration of infection, including the clinically quiescent phase of disease. The level of this active viral replication correlates directly with disease progression and survival. The advent of combination therapeutics for HIV-1 (i.e., highly active antiretroviral therapy [HAART]) has led to dramatic reductions in viral replication in vivo and morbidity and mortality, at least in the developed world.     

Chemokine receptors and HIV-1 infection

Chemokines are now known to function as regulatory molecules in leukocyte maturation, in traffic and homing of lymphocytes, and in the development of lymphoid tissues. Besides these functions in the immune system, certain chemokine receptors also function as co-receptors for human immunodeficiency virus type-1 (HIV-1) entry into CD4+ lymphocytes. CCR5 and CXCR4 are the major co-receptors for macrophage tropic and T-cell line tropic viral isolates, respectively. Here, we review recent studies on the relationship between chemokine receptors and HIV-1 infection. Elucidating the roles that chemokines and chemokine receptors play in the course of HIV-1 infection may substantially enhance our understanding on the HIV-1 pathogenesis, and perhaps help the discovery of drug candidates for therapeutic intervention of HIV infection.     

Reducing HIV-1 transmission through prevention strategies targeting HIV-1-seropositive individuals

Prevention efforts for HIV-1 have traditionally focused on those at risk for acquiring the virus. Recently, there has been growing interest in directing prevention efforts towards HIV-1-seropositive individuals, who are seeking care in increasing numbers as a result of improving access to antiretroviral therapy in resource-limited countries. Biomedical interventions aimed at reducing the spread of HIV-1 by targeting those at risk for transmitting the virus will be guided in part by an understanding of the bidirectional interactions between HIV-1 and other sexually transmitted diseases (STDs). Among those who are infected with HIV-1, STDs are common, and immunosuppression may further increase STD risk. In turn, the presence of an STD increases the concentration of HIV-1 in genital mucosal secretions. Both antiretroviral therapy and treatment of STDs can lower genital HIV-1 concentrations, suggesting that these approaches may reduce infectivity. Thus, the growing availability of HIV-1 and STD treatment in the countries most affected by the HIV-1 epidemic provides a unique and important opportunity to develop prevention strategies that target HIV-1/STD interactions at multiple levels. Further work is urgently needed to develop, test and implement comprehensive strategies for prevention in positives.     

HIV-1 RNA and viral load

Viral load monitoring has become the standard of care in clinical practice to assess risk for disease progression and to monitor treatment response. Furthermore, viral load monitoring has contributed greatly to the understanding of HIV disease pathogenesis and response to various antiretroviral regimens, and has broadened its applications to include blood bank screening. The assays that are currently available are more sensitive, precise, and robust. There is now a better understanding of their limitations and the clinical scenarios and assay performance issues that result in variations of viral load results.     

HIV-1 genotypic and phenotypic resistance

Antiretroviral failure caused by the development of drug resistance in HIV-1 is an increasingly common clinical problem. Two types of resistance assays are available to clinicians. Genotypic assays determine the presence of mutations associated with drug resistance. The interpretation of mutations is often complicated, however, and may require expert opinion. Phenotypic assays provide a direct measure of the drug susceptibility of the virus. The magnitude of increase, however, in viral drug inhibitory concentration that is predictive of clinical drug failure remains unknown for several antiretroviral drugs. The mutational patterns underlying resistance to each antiretroviral drug are often diverse, and cross-resistance patterns within each of the currently available classes are complex. Currently, resistance testing is recommended for patients who have virologic failure on an antiretroviral regimen. Furthermore, testing should also be considered in treatment-native patients when the prevalence of transmitted drug-resistant virus is expected to be high.