Immune response and AIDS

This article presents an interview with Dr. Sharilyn K. Stanley regarding her study on how immune system activation boosts HIV replication in HIV-infected people. Asked to give a brief outline of the study, Stanley noted that a single booster dose of tetanus toxoid was given to HIV-infected and uninfected volunteers in order to stimulate their immune system. In the evaluation that followed, high levels of HIV circulating in the blood of HIV-infected patients and uninfected individuals were found. In terms of insights gained into the cellular environment and how the immune system works, Stanley specified that previous work has shown the regulation of HIV expression by cytokines, the molecules that the immune system uses to signal itself. Moreover, Stanley comments that by rapidly and effectively diagnosing and treating infections associated with HIV, a huge increase in virus may be avoided when the immune systems of HIV-infected people are activated. Furthermore, future studies complementing the findings of the study and proposed studies in developing countries were revealed by Stanley.     

Mucosal innate immunity as a determinant of HIV susceptibility

Most human immunodeficiency virus (HIV) is acquired during sex, across a mucosal membrane. Despite many advances in our understanding of HIV pathogenesis, the initial events during mucosal transmission have been poorly characterized, and a better understanding of these events will probably be a key to the development of successful microbicide(s) and/or a preventative HIV vaccine. While a vast majority of mucosal HIV exposures do not result in productive infection, implying that innate mucosal immune defenses are highly protective, failure of these mucosal defenses resulted in over 3 million new HIV infections in 2006. We review recent findings regarding HIV mucosal immunopathogenesis, emphasizing the importance of innate immunity in natural protection from infection, and examine how natural or induced perturbations in the mucosal innate system may underpin HIV transmission. Given the great challenges to the development of HIV microbicides and vaccines, identification and enhancement of 'natural' innate immune defenses present attractive avenues for development of safe, non-toxic microbicides.     

New discoveries in the treatment of AIDS-related cancers

AIDS-related cancer research may also lead to advances in cancer treatment in HIV-negative people. Significant findings in the treatment of AIDS-related cancers were presented at the American Society of Clinical Oncology meeting. Researchers at the Center for AIDS Research at the University of California, San Diego, found that granulocyte-colony stimulating factor (G-CSF/Neupogen) was well-tolerated when administered to patients with AIDS. G-CSF could be administered to enhance the immune system rather than having patients undergo bone marrow transplantation. Vinorelbine (Navelbine), a chemotherapeutic agent, could be effective for the treatment of HIV-positive patients with previously-treated Kaposi's sarcoma (KS), according to Dr. Domenico Erranto of the Centro Di Riferimento Oncologia, Italy. The effects of commonly-used medications, particularly immunosupressive chemotherapy agents, on HIV viral replication are unknown. Preliminary findings from the AIDS Malignancy Program at the Illinois Masonic Cancer Center in Chicago suggest that standard chemotherapeutic agents do not significantly affect HIV activity when used in combination with anti-HIV drug therapies.     

"Can HIV be eradicated from an infected individual?" Piot,Ho and scientific community meet at 4th Retroviral Conference

More than 2300 medical and scientific professionals attended the 4th Conference on Retroviruses and Opportunistic Infection held in Washington, DC, during January 22-26, 1997, to discuss the latest information on treatment for HIV/AIDS and opportunistic infections. The keynote speakers were Dr. David Ho, a researcher at the Aaron Diamond AIDS Institute, and Dr. Peter Piot, Director of UNAIDS. Dr. Ho told the audience that reasons exist to be hopeful about prolonging the life of people with AIDS even though HIV has not yet been eliminated from any infected individual. He urged the media to carefully and accurately portray HIV/AIDS, and stressed that there is no cure for AIDS and that safer sex practices should be maintained in order to prevent the sexual transmission of HIV. In his address, Dr. Piot considered how HIV/AIDS treatment and care options translate to the reality of developing countries in which 90% of all HIV/AIDS cases reside. Recognizing researchers' accomplishments in developing treatment therapies against HIV/AIDS, Piot urged them to focus upon the development of preventive technology, including microbicides, vaccines, and a way to prevent mother-to-fetus HIV transmission. Dr. Piot also discussed a proposed UNAIDS plan to make advanced therapies against HIV/AIDS available in developing countries.     

Pathogenesis puzzle

Gaining an understanding of how HIV infects cells and replicates, and how quickly and constantly this replication occurs, may enable physicians and researchers to treat individuals more effectively. Among other theories discussed, some scientists believe that CD4 T cells, which are specific to fighting HIV, are still abundantly present in individuals with active HIV infection. They suggest that the immune system continually responds to the virus even as CD4 T cells are depleted. It is not yet known how the immune system eventually becomes debilitated as virus replication continues. Efforts are underway to further study the immune system and identify ways to enhance its performance. A glossary of terms used in the article is provided.     

Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia

HIV-infected humans and SIV-infected rhesus macaques who remain healthy despite long-term infection exhibit exceptionally low levels of virus replication and active antiviral cellular immune responses. In contrast, sooty mangabey monkeys that represent natural hosts for SIV infection do not develop AIDS despite high levels of virus replication and limited antiviral CD8(+) T cell responses. We report here that SIV-infected mangabeys maintain preserved T lymphocyte populations and regenerative capacity and manifest far lower levels of aberrant immune activation and apoptosis than are seen in pathogenic SIV and HIV infections. These data suggest that direct consequences of virus replication alone cannot account for progressive CD4(+) T cell depletion leading to AIDS. Rather, attenuated immune activation enables SIV-infected mangabeys to avoid the bystander damage seen in pathogenic infections and protects them from developing AIDS.     

The innate immune system and HIV pathogenesis

Innate immunity represents the first line of defense against microbial infections. The innate immune system is activated by conserved structures present on most pathogens and profoundly regulates subsequent adaptive immune responses. HIV is notorious for evading and disrupting the immune system. Although HIV directly targets and gradually destroys the adaptive immunity, it has become clear that the virus also perturbs the components of the innate immune system. In this paper, we review the role of two innate lymphocyte subsets, natural killer and natural killer T cells, that are disrupted during HIV infection.     

The innate immune system and HIV pathogenesis

Innate immunity represents the first line of defense against microbial infections. The innate immune system is activated by conserved structures present on most pathogens and profoundly regulates subsequent adaptive immune responses. HIV is notorious for evading and disrupting the immune system. Although HIV directly targets and gradually destroys the adaptive immunity, it has become clear that the virus also perturbs the components of the innate immune system. In this paper, we review the role of two innate lymphocyte subsets, natural killer and natural killer T cells, that are disrupted during HIV infection.     

Regulation of Mucosal Immunity in the Female Reproductive Tract: The Role of Sex Hormones in Immune Protection Against Sexually Transmitted Pathogens

The immune system in the female reproductive tract (FRT) does not mount an attack against human immunodeficiency virus (HIV) or other sexually transmitted infections (STI) with a single endogenously produced microbicide or with a single arm of the immune system. Instead, the body deploys dozens of innate antimicrobials to the secretions of the FRT. Working together, these antimicrobials along with mucosal antibodies attack viral, bacterial, and fungal targets. Within the FRT, the unique challenges of protection against sexually transmitted pathogens coupled with the need to sustain the development of an allogeneic fetus, has evolved in such a way that sex hormones precisely regulate immune function to accomplish both tasks. The studies presented in this review demonstrate that estradiol (E₂) and progesterone secreted during the menstrual cycle act both directly and indirectly on epithelial cells, fibroblasts and immune cells in the reproductive tract to modify immune function in a way that is unique to specific sites throughout the FRT. As presented in this review, studies from our laboratory and others demonstrate that the innate and adaptive immune systems are under hormonal control, that protection varies with the stage of the menstrual cycle and as such, is dampened during the secretory stage of the cycle to optimize conditions for fertilization and pregnancy. In doing so, a window of STI vulnerability is created during which potential pathogens including HIV enter the reproductive tract to infect host targets.     

Small alveolar macrophages are infected preferentially by HIV and exhibit impaired phagocytic function

HIV-1-infected persons are at higher risk of lower respiratory tract infections than HIV-1-uninfected individuals. This suggests strongly that HIV-infected persons have specific impairment of pulmonary immune responses, but current understanding of how HIV alters pulmonary immunity is incomplete. Alveolar macrophages (AMs), comprising small and large macrophages, are major effectors of innate immunity in the lung. We postulated that HIV-1 impairs pulmonary innate immunity through impairment of AM physiological functions. AMs were obtained by bronchoalveolar lavage from healthy, asymptomatic, antiretroviral therapy-naive HIV-1-infected and HIV-1-uninfected adults. We used novel assays to detect in vivo HIV-infected AMs and to assess AM functions based on the HIV infection status of individual cells. We show that HIV has differential effects on key AM physiological functions, whereby small AMs are infected preferentially by the virus, resulting in selective impairment of phagocytic function. In contrast, HIV has a more generalized effect on AM proteolysis, which does not require direct viral infection. These findings provide new insights into how HIV alters pulmonary innate immunity and the phenotype of AMs that harbors the virus. They underscore the need to clear this HIV reservoir to improve pulmonary immunity and reduce the high incidence of lower respiratory tract infections in HIV-1-infected individuals.     

Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS

NK cells play an important role in controlling viral infections. They can kill virus-infected cells directly as well as indirectly via antibody-dependent, cell-mediated cytotoxicity. They need no prior sensitization and expansion for this killing. NK cells are also considered as important regulators of antiviral immune responses. They do so by secreting a multitude of soluble mediators and by directly interacting with other immune cells, e.g., dendritic cells. NK cells do not possess a single well-defined receptor to recognize antigens on target cells. Instead, they express an array of inhibitory and activating receptors and coreceptors, which bind to their cognate ligands expressed on the surface of target cells. These ligands include classical and nonclassical MHC class I antigens, MHC-like proteins, and a variety of other self- and virus-derived molecules. They may be expressed constitutively and/or de novo on the surface of virus-infected cells. NK cell receptors (NKRs) of the killer-cell Ig-like receptor (KIR) family, like their MHC class I ligands, are highly polymorphic. Several recent studies suggest that epistatic interactions between certain KIR and MHC class I genes may determine innate resistance of the host to viral infections, including HIV. In the first part of this review article, we provide an overview of the current state of knowledge of NK cell immunobiology and describe how NKR genes, alone and in combination with HLA genes, may determine genetic resistance/susceptibilty to HIV infection and the development of AIDS in humans.     

Markers predicting progression of human immunodeficiency virus-related disease.

Human immunodeficiency virus (HIV) interacts with the immune system throughout the course of infection. For most of the disease process, HIV activates the immune system, and the degree of activation can be assessed by measuring serum levels of molecules such as beta 2-microglobulin and neopterin, as well as other serum and cell surface phenotype markers. The levels of some of these markers correlate with clinical progression of HIV disease, and these markers may be useful as surrogate markers for development of clinical AIDS. Because the likelihood and timing of development of clinical AIDS following seroconversion, for any particular individual, are not readily predictable, the use of nonclinical disease markers has become critically important to patient management. Surrogate markers of HIV infection are, by definition, measurable traits that correlate with disease progression. An ideal marker should identify patients at highest risk of disease progression, provide information on how long an individual has been infected, help in staging HIV disease, predict development of opportunistic infections associated with AIDS, monitor the therapeutic efficacy of immunomodulating or antiviral treatments, and the easily quantifiable, reliable, clinically available, and affordable. This review examines the current state of knowledge and the role of surrogate markers in the natural history and treatment of HIV infection. The clinical usefulness of each marker is assessed with respect to the criteria outlined for the ideal surrogate marker for HIV disease progression.     

HIV-1 proteins in infected cells determine the presentation of viral peptides by HLA class I and class II molecules and the nature of the cellular and humoral antiviral immune responses—A review

The goals of molecular virology and immunology during the second half of the 20th century have been to provide the conceptual approaches and the tools for the development of safe and efficient virus vaccines for the human population. The success of the vaccination approach to prevent virus epidemics was attributed to the ability of inactivated and live virus vaccines to induce a humoral immune response and to produce antiviral neutralizing antibodies in the vaccinees. The successful development of antiviral vaccines and their application to most of the human population led to a marked decrease in virus epidemics around the globe. Despite this remarkable achievement, the developing epidemics of HIV-caused AIDS (accompanied by activation of latent herpesviruses in AIDS patients), epidemics of Dengue fever, and infections with respiratory syncytial virus may indicate that conventional approaches to the development of virus vaccines that induce antiviral humoral responses may not suffice. This may indicate that virus vaccines that induce a cellular immune response, leading to the destruction of virus-infected cells by CD8⁺ cytotoxic T cells (CTLs), may be needed. Antiviral CD8⁺ CTLs are induced by viral peptides presented within the peptide binding grooves of HLA class I molecules present on the surface of infected cells. Studies in the last decade provided an insight into the presentation of viral peptides by HLA class I molecules to CD8⁺ T cells. These studies are here reviewed, together with a review of the molecular events of virus replication, to obtain an overview of how viral peptides associate with the HLA class I molecules. A similar review is provided on the molecular pathway by which viral proteins, used as subunit vaccines or inactivated virus particles, are taken up by endosomes in the endosome pathway and are processed by proteolytic enzymes into peptides that interact with HLA class II molecules during their transport to the plasma membrane of antigen-presenting cells. Such peptides are identified by T-cell receptors present on the plasma membrane of CD4⁺ T helper cells. The need to develop viral synthetic peptides that will have the correct amino acid motifs for binding to HLA class I A, B, and C haplotypes is reviewed.The development of HIV vaccines that will stimulate, in an uninfected individual, the humoral (antibody) and cellular (CTL) immune defenses against HIV and HIV-infected cells, respectively, and may lead to protection from primary HIV infection are discussed. The need to eliminate the release of HIV virions from infected cells introduced by an infected donor to an uninfected recipient may require both the humoral and cellular immune responses. However, such CTLs may fail to identify HIV-infected cells with integrated HIV proviral DNA that do not express viral genes and proteins. Based on reported results on the immunization of monkeys with uninfected cells, which prevented infection with SIV grown in the same type of cells, it may be possible to consider immunization of specific human populations against HLA haplotypes prevalent in HIV-infected donors. Since HIV virions may carry the HLA class I molecules present in the infected donors' cells, synthesis of CTLs to the mutated amino acid sequence in peptide binding grooves of the foreign HLA haplotypes may induce anti-HLA CTLs in the immunized individual, which may destroy HIV-infected, virus synthesizing donor cells, as well as donor cells containing latent proviral DNA. Such anti-foreign HLA CTLs may prevent the release of virions from the infecting donor's cells. The importance of HLA haplotypes for protection against HIV will be discussed.Dedicated to the memory of Dr. Albert Sabin (1906–1993).     

Regulatory T cells in virus infections

Summary: This review discusses situations when the magnitude and function of immune responses to virus infection are influenced by regulatory T cells (Tregs). The focus is on CD4⁺CD25⁺ forkhead box protein 3⁺ natural Tregs (nTregs). The immune response may be limited in magnitude and efficacy when animals with normal nTreg function are infected with virus. This limitation can be observed both in vitro and in vivo. In the case of herpes simplex virus (HSV), animals depleted of nTregs prior to infection more effectively control the virus. With some virus infections, Treg responses (either nTregs or interleukin‐10‐dependent adaptive Tregs) appear to contribute to immune dysfunction, accounting for viral persistence and chronic tissue damage. This may occur with hepatitis C virus and some retrovirus infections that include human immunodeficiency virus (HIV). Under other circumstances, the nTreg response is judged to be beneficial, as it may help limit the severity of tissue damage associated with an immunoinflammatory reaction to virus infection. Such a situation occurs in HSV‐induced immunopathological lesions in the eye. With HIV, nTregs may help limit chronic immune activation that may precede collapse of the immune system. This review also discusses how virus infections become recognized by nTreg responses and how such responses might be manipulated to increase immunity or to limit virus‐induced immunopathology.     

Comparing HIV‐1 and HIV‐2 infection: Lessons for viral immunopathogenesis

HIV‐1 and HIV‐2 share many similarities including their basic gene arrangement, modes of transmission, intracellular replication pathways and clinical consequences: both result in AIDS. However, HIV‐2 is characterised by lower transmissibility and reduced likelihood of progression to AIDS. The underlying mechanistic differences between these two infections illuminate broader issues of retroviral pathogenesis, which remain incompletely understood. Comparisons between these two infections from epidemiological, clinical, virologic and immunologic viewpoints provide a basis for hypothesis generation and testing in this ‘natural experiment’ in viral pathogenesis. In terms of epidemiology, HIV‐2 remains largely confined to West Africa, whereas HIV‐1 extends worldwide. Clinically, HIV‐2 infected individuals seem to dichotomise, most remaining long‐term non‐progressors, whereas most HIV‐1 infected individuals progress. When clinical progression occurs, both diseases demonstrate very similar pathological processes, although progression in HIV‐2 occurs at higher CD4 counts. Plasma viral loads are consistently lower in HIV‐2, as are average levels of immune activation. Significant differences exist between the two infections in all components of the immune system. For example, cellular responses to HIV‐2 tend to be more polyfunctional and produce more IL‐2; humoral responses appear broader with lower magnitude intratype neutralisation responses; innate responses appear more robust, possibly through differential effects of tripartite motif protein isoform 5 alpha. Overall, the immune response to HIV‐2 appears more protective against disease progression suggesting that pivotal immune factors limit viral pathology. If such immune responses could be replicated or induced in HIV‐1 infected patients, they might extend survival and reduce requirements for antiretroviral therapy. Copyright © 2013 John Wiley & Sons, Ltd.     

The lectin pathway of complement: Advantage or disadvantage in HIV pathogenesis?

The pattern recognition molecules of the lectin complement pathway are important components of the innate immune system with known functions in host–virus interactions. This paper summarizes current knowledge of how these intriguing molecules, including mannose-binding lectin (MBL), Ficolin-1, -2 and -3, and collectin-11 (CL-11) may influence HIV-pathogenesis. It has been demonstrated that MBL is capable of binding and neutralizing HIV and may affect host susceptibility to HIV infection and disease progression. In addition, MBL may cause variations in the host immune response against HIV. Ficolin-1, -2 and -3 and CL-11 could have similar functions in HIV infection as the ficolins have been shown to play a role in other viral infections, and CL-11 resembles MBL and the ficolins in structure and binding capacity.     

Immune system activation boosts HIV replication in HIV-infected people

According to a study, investigators at the National Institute of Allergy and Infectious Diseases discovered that activation of the immune system by other stimuli boosts HIV replication in HIV-infected people. Dr. Sharilyn Stanley and colleagues inoculated 13 asymptomatic HIV-infected people and 10 uninfected volunteers with tetanus booster shots to stimulate their immune system. Blood samples were drawn on the day of the injection and 3, 7, 14, 21, 28, and 42 days later. Findings showed that the amount of HIV in the blood streams of HIV-infected subjects increased 2- to 36-fold following immunization. Notably, the virus was much more readily grown from the blood cells of 9 of the HIV-infected patients after immunization. In addition, examinations of the immune system cells of the uninfected volunteers found that cells from 7 of these 10 people were more easily infected with HIV in the test tube after immunization than before immunization. Overall, data suggest that ongoing immune activation may play a part in HIV pathogenesis and may also enhance susceptibility of uninfected people to HIV. However, it was noted that the increases in HIV following immunization were transient and that the protection afforded by immunization most likely outweighs the potential risks resulting from the transient increase in HIV. Development of therapies against microbes that contribute to a state of chronic and persistent immune activation in HIV-infected people is recommended.