Human cytomegalovirus immunity and immune evasion

Human cytomegalovirus (HCMV) infection induces both innate immune responses including Natural Killer cells as well as adaptive humoral and cell mediated (CD4+ helper, CD8+ cytotoxic and γδ T cell) responses which lead to the resolution of acute primary infection. Despite such a robust primary immune response, HCMV is still able to establish latency. Long term memory T cell responses are maintained at high frequency and are thought to prevent clinical disease following periodic reactivation of the virus. As such, a balance is established between the immune response and viral reactivation. Loss of this balance in the immunocompromised host can lead to unchecked viral replication following reactivation of latent virus, with consequent disease and mortality. HCMV encodes multiple immune evasion mechanisms that target both the innate and acquired immune system. This article describes the current understanding of Natural killer cell, antibody and T cell mediated immune responses and the mechanisms that the virus utilizes to subvert these responses.     

Decimated or missing in action: CD4+ T cells as targets and effectors in the pathogenesis of primary HIV infection

HIV infection provides a unique challenge to the immune system. CD4+ T cells are targets of infection, whereas effective anti-HIV CD4+ T-cell responses are essential for sustained viral control. There is increasing evidence of preferential depletion of certain subsets of CD4+ T cells. Studies of tissues have demonstrated preferential depletion of CD4+ T cells from gastrointestinal lymphoid tissue (GALT). Simian immunodeficiency virus infection of macaques results in extensive depletion of CD4+ memory T cells from GALT within weeks of infection. Other macaque studies suggest this rapid, profound depletion is generalized across all lymphoid tissue. Although these models provide insight into possible pathogenic processes, these results cannot be directly extrapolated to HIV infection in humans. Although there is depletion of CD4+ T cell memory cells early in HIV infection, the mechanism of this depletion appears to be related to increased cell turnover, chronicity of antigen exposure, and ineffective production of central memory CD4+ T cells rather than only direct cell depletion.     

HIV-1 infection: is it time to reconsider our concepts?

The long asymptomatic phase of HIV infection is critical in the progression to AIDS. It probably reflects an ancestral relationship with lentiviruses stemming from the primate-simian immunodeficiency virus evolutionary pathway leading to an idiosyncratic immune tolerance, which needs to be understood if effective vaccines are to be rationally designed. The majority of CD4+ T cells that die due to HIV-1 in the asymptomatic phase are not infected with the virus. Transmission of the predominant HIV-1 R5 variants to T cells is mediated by infected monocyte-derived macrophages. The two cell populations come into intimate contact mainly in the lymph nodes during antigen presentation where there is also active viral replication. We propose that HIV exploits antigen presentation to access target T cells and evade immune surveillance. This is achieved at the assembly point of an immunological synapse between an antigen presenting, HIV-1-infected macrophage and a responding effector/memory CD4+ T cell. Viral envelope gp120 glycoproteins proximal to MHC II molecules cross-link with T cell CD4 molecules, thus establishing a supra molecular immuno-viral synapse. The interaction results in conformational changes of gp120 exposing its V3 domain. Ionic interaction of this domain with the synapse-recruited chemokine receptor CCR5 dimerizes the receptor triggering intracellular signals that contribute to T cell receptor transactivation pathways and subsequent enhancement of T cell activation. HIV-downregulated MHC II gives weak immune complexes. Disruption of the immuno-viral synapse before completion of cell entry is a frequent outcome condemning the responding T cell to a premature activation-induced T cell death. Information on the assembly, mechanistic and functional interactions at the immuno-viral synapses may well assist in elucidating new strategies to combat HIV infection.     

高效抗病毒治疗促使艾滋病患者免疫功能重建

艾滋病的特征是ＨＩＶ 1感染人体后 ,造成ＣＤ4 +Ｔ淋巴细胞数量进行性减少、细胞免疫功能损害 ,最后导致艾滋病 (ＡＩＤＳ)。先前的研究表明这种免疫功能的丧失是不可逆转的 ,抗ＨＩＶ病毒治疗仅能控制或减缓其进展。近年来 ,由于强效联合抗病毒治疗 (ＨＡＡＲＴ)的应用 ,艾滋病的发病率和死亡率均较前明显下降 (指西方国家 )。说明ＨＡＡＲＴ不仅能有效的控制ＨＩＶ 1的复制 ,并能使艾滋病病人的免疫功能得到恢复。这种ＨＡＡＲＴ使艾滋病病人免疫功能重建的假说最近被一组法国研究人员证实 ,艾滋病的免疫重建规律是 :(1)治疗早期ＣＤ4 +…     

Viral and host factors in the pathogenesis of HIV infection

Recent studies suggest that the pathogenesis of HIV infection and AIDS involves two distinct phases. During acute infection, massive depletion of CD4+CCR5+ memory T cells within the mucosal-associated lymphoid tissue leads to major and potentially irreversible damage to CD4+ T-cell-mediated immune functions. The emergence of potent, but ultimately ineffective, cell-mediated and humoral responses to HIV leads to the chronic phase of infection, which is characterized by partial control of viral replication, chronic immune activation, progressive decline of the na?ve and memory T-cell pool, and systemic CD4+ T-cell depletion. The identification of these two pathogenic phases of HIV infection could have important implications in terms of HIV therapy and vaccine development.     

Cellular immunity and memory to respiratory virus infections

Respiratory virus infections, such as those caused by influenza and parainfluenza viruses, are a major cause of morbidity and mortality worldwide. Current vaccines against these pathogensrely on the induction of humoral immune responses that target viral coat proteins. Although this type of immunity provides solid protection against homologous virus strains, it is ineffective against heterologous virus strains that express serologically distinct coat proteins. In contrast, cellular immune responses can target internal an tigens that are shared between heterologous viral strains. This form of immunity, sometimes referred to as heterosubtypic immunity, can mediate a substantial degree of protection. Thus, vaccines that emphasize cellular immune responses would be a valuable complement to available humoral vaccines. However, we only have a rudimentary understanding of which T cell subsets mediate protective immunity, how T cell memory isestablished and maintained, how that memory is recalled in a secondary infection, and why cellular immunity wanes rapidly with time. Here we review the role of CD4⁺ and CD8⁺ T cells in the recall response to influenza and parain fluenza viruses. In particular we focus on the recent observation that substantial numbers of memory T cells are established in the lung tissues and discuss the potential role of these cells in mediating a recall response. A thorough understanding of the cellular immune response to infection in the lungs is essential for future vaccine development.     

Intestinal double-positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines

Peripheral blood and intestinal CD4+CD8+ double-positive (DP) T cells have been described in several species including humans, but their function and immunophenotypic characteristics are still not clearly understood. Here we demonstrate that DP T cells are abundant in the intestinal lamina propria of normal rhesus macaques (Macaca mulatta). Moreover, DP T cells have a memory phenotype and are capable of producing different and/or higher levels of cytokines and chemokines in response to mitogen stimulation compared to CD4+ single-positive T cells. Intestinal DP T cells are also highly activated and have higher expression of CCR5, which makes them preferred targets for simian immunodeficiency virus/HIV infection. Increased levels of CD69, CD25 and HLA-DR, and lower CD62L expression were found on intestinal DP T cells populations compared to CD4+ single-positive T cells. Collectively, these findings demonstrate that intestinal and peripheral blood DP T cells are effector cells and may be important in regulating immune responses, which distinguishes them from the immature DP cells found in the thymus. Finally, these intestinal DP T cells may be important target cells for HIV infection and replication due to their activation, memory phenotype and high expression of CCR5.     

High proportion of PD‐1‐expressing CD4+ T cells in adipose tissue constitutes an immunomodulatory microenvironment that may support HIV persistence

We and others have demonstrated that adipose tissue is a reservoir for HIV. Evaluation of the mechanisms responsible for viral persistence may lead to ways of reducing these reservoirs. Here, we evaluated the immune characteristics of adipose tissue in HIV‐infected patients receiving antiretroviral therapy (ART) and in non‐HIV‐infected patients. We notably sought to determine whether adipose tissue's intrinsic properties and/or HIV induced alteration of the tissue environment may favour viral persistence. ART‐controlled HIV infection was associated with a difference in the CD4/CD8 T‐cell ratio and an elevated proportion of Treg cells in subcutaneous adipose tissue. No changes in Th1, Th2 and Th17 cell proportions or activation markers expression on T cell (Ki‐67, HLA‐DR) could be detected, and the percentage of CD69‐expressing resident memory CD4⁺ T cells was not affected. Overall, our results indicate that adipose‐tissue‐resident CD4⁺ T cells are not extensively activated during HIV infection. PD‐1 was expressed by a high proportion of tissue‐resident memory CD4⁺ T cells in both HIV‐infected patients and non‐HIV‐infected patients. Our findings suggest that adipose tissue's intrinsic immunomodulatory properties may limit immune activation and thus may strongly contribute to viral persistence.     

The relationship of T-regulatory cell subsets to disease stage, immune activation, and pathogen-specific immunity in HIV infection

BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with abnormalities in T-regulatory (T-reg) cells, but the effect of HIV on the naive (CD45RO-) and memory (CD45RO) CD25+CD127loCD4+ T-reg cell subsets has not been defined. METHODS: We measured the absolute number and relative percentage of total, naive, and memory T-reg cells in HIV-infected subjects and compared these parameters with their CD4+ T cells, viral load, levels of immune activation, and pathogen-specific immunity. RESULTS: HIV infection was associated with an increased percentage of memory CD25+CD127loCD4+ T-reg cells and a decreased percentage of naive CD25+CD127loCD4+ T-reg cells as CD4+ T cells declined. The level of HIV viremia inversely correlated with total, memory, and naive CD25+CD127loCD4+ T-reg cell numbers and percentage of naive CD25+CD127loCD4+ T-reg cells. Lower total, memory, and naive CD25+CD127loCD4+ T-cell numbers were associated with higher levels of immune activation, whereas a higher percentage of CD25+CD127loCD4+ T-reg cells was associated with lower Candida- and HIV-specific immune responses. CONCLUSIONS: These observations suggest that CD25+CD127loCD4+ T-reg cells contribute to the immunodeficiency seen in HIV disease.     

Purinergic signaling and human immunodeficiency virus/acquired immune deficiency syndrome: From viral entry to therapy

Human immunodeficiency virus(HIV) infection is a serious condition associated to severe immune dysfunction and immunodeficiency. Mechanisms involved in HIV-associated immune activation, inflammation and loss of CD4+ T cells have been extensively studied, including those concerning purinergic signaling pathways. Purinergic signaling components are involved in viral entry and replication and disease progression. Research involving the participation of purinergic signaling in HIV infection has been not only important to elucidate disease mechanisms but also to introduce new approaches to therapy. The involvement of purinergic signaling in the pathogenesis of HIV infection and its implications in the control of the HIV infection are reviewed in this paper.     

The roles of resident,central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

Immunological memory provides rapid protection to pathogens previously encountered through infection or vaccination. CD4 T‐cells play a central role in all adaptive immune responses. Vaccines must, therefore, activate CD4 T‐cells if they are to generate protective immunity. For many diseases, we do not have effective vaccines. These include human immunodeficiency virus (HIV), tuberculosis and malaria, which are responsible for many millions of deaths each year across the globe. CD4 T‐cells play many different roles during the immune response coordinating the actions of many other cells. In order to harness the diverse protective effects of memory CD4 T‐cells, we need to understand how memory CD4 T‐cells are generated and how they protect the host. Here we review recent findings on the location of different subsets of memory CD4 T‐cells that are found in peripheral tissues (tissue resident memory T‐cells) and in the circulation (central and effector memory T‐cells). We discuss the generation of these cells, and the evidence that demonstrates how they provide immune protection in animal and human challenge models.     

Can antiretroviral therapy ever be stopped?

A pool of latently infected CD4+ T cells is established within the first few weeks of HIV infection. Because these memory T cells are inactive, the viral DNA integrated into their chromosomes remains invisible to immune surveillance and to antiretrovirals. Research shows that this reservoir of infected memory T cells does not decay in a clinically meaningful time frame--that is, within 60 years--in patients being treated with potent combination antiretrovirals. Even a hypothetical regimen that prevents any new infection of cells would not hasten the decay of this latent reservoir. Treatments that activate this reservoir have been studied in patients with suppressed viremia, but such interventions are highly toxic and have not succeeded so far. Studying rare individuals who manage to control activation of these latent cells may provide important clues to long-term control of HIV infection.     

Differential regulation of CXCR4 and CCR5 expression by interleukin (IL)-4 and IL-13 is associated with inhibition of chemotaxis and human immunodeficiency Virus (HIV) type 1 replication but not HIV entry into human monocytes

Chemokine receptors CXCR4 and CCR5 play a key role in Human Immunodeficiency Virus (HIV) entry into CD4+ monocytic cells. Alteration in the expression levels of these receptors by immunoregulatory cytokines may influence viral entry and hence susceptibility to HIV infection, viral tropism, and disease progression. Helper T cell type 2 (Th2) cytokines interleukin (IL)-4 and IL-13, which share a subunit of their receptor components and exhibit similar biological effects, have been shown to play a key role in HIV infection and disease progression. In this study, we investigated the effects of IL-4 and IL-13 on the expression of CXCR4 and CCR5, and the biological implications of alteration of CXCR4 and CCR5 regulation on monocytic cells with respect to their migration in response to chemokines, HIV entry, and its replication. The results suggest that both IL-4 and IL-13 inhibited the expression of CXCR4, in contrast to CCR5, which was inhibited by IL-13 alone. The downregulation of CXCR4 and CCR5 was correspondingly associated with the inhibition of their respective ligand-induced chemotaxis. Although IL-13 inhibited the expression of both CXCR4 and CCR5, this downregulation of chemokine receptor expression was not sufficient to prevent virus entry. Furthermore, both IL-4 and IL-13 inhibited viral replication in monocytic cells, suggesting that inhibition of chemokine receptor expression per se by these cytokines may not be sufficient to prevent virus entry, and indicating these cytokines may be inhibiting viral replication by targeting pathways subsequent to virus entry.     

Inhibition of human immunodeficiency virus infection in monocytes by monoclonal antibodies against leukocyte adhesion molecules.

CD4 is the surface receptor for HIV envelope. Some evidence exists, however, that other cell surface receptors may be involved in viral entry subsequent to the initial binding of gp120 to CD4. Antibodies to leukocyte integrin LFA-1, a major component of intercellular adhesive interactions, have been shown to inhibit HIV-induced syncytia formation. Using a stringent system for in vitro HIV infection of human leukocytes, we examine the ability of some monoclonal antibodies (mAb) against various adhesion-related molecules to block or partially inhibit productive viral replication. HIV-1 infection of target monocytes or T cells by cell-free virus was blocked completely or partially by some mAb that prevent cell-cell interactions (CD4, HLA-DR, LFA-1, LFA-3), but not by others (ICAM-1, MAC-1, gp150.95, CD2, CD3, CD14). The capacity for mAb to block HIV infection appears to be epitope-specific, and does not relate to the ability to block homotypic adhesion. HIV transmission from infected cells was more difficult to block than was infection by cell-free virus. Adhesion molecules may be involved in facilitating early stages of HIV infection, following gp120/CD4 binding but prior to viral integration, in a manner distinct from cell-cell adhesion.     

T cell virological synapses and HIV-1 pathogenesis

Human immunodeficiency virus type 1 is the cause of a modern global pandemic associated with progressive acquired immune deficiency. The infection is characterized by the loss of the primary target of viral infection, the CD4+ T cell. The measurement of plasma viremia in patients can predict the rate of CD4+ cell decline; however, it is not clear whether this cell-free plasma virus represents the engine that drives viral spread. Active viral replication is mainly observed within lymphoid tissues that are hotbeds of cell–cell interactions that initiate and organize immune responses. It is well established that cell–cell interactions enhance viral spread in vitro. Dendritic cell–T cell interactions, which lie at the heart of adaptive immune responses, enhance viral infection in vitro. Interactions between infected and uninfected CD4+ T cells are a dominant route of viral spread in vitro and are likely to play a central role in viral dissemination in vivo. Future studies will test existing paradigms of HIV-1 dissemination to determine whether virus-transmitting contacts between infected and uninfected T cells called virological synapses are the dominant mode of viral spread in vivo. Here, we review the status of our understanding of this mode of infection with a focus on T cell–T cell interactions and examine how it may explain resistance to neutralizing antibodies and or the generation of genetic diversity of HIV.     

Natural analogue peptides of an HIV-1 GP120 T-helper epitope antagonize response of GP120-specific human CD4 T-cell clones

Neutralizing antibodies and specific cytotoxic T lymphocytes (CTL) may contribute to controlling viral spread, and ideally, to virus clearance in HIV infection. Both effector mechanisms depend on specific CD4 T-helper (Th) cells. Nevertheless, HIV hypervariability facilitates appearance of escape mutants for antibodies and for CTL responses. Here we also show that natural mutations (i.e., from sequences of different HIV strains) in an immunodominant Th epitope recognized by human CD4 clones specific for the envelope glycoprotein gp120 escape CD4 T-cell recognition. Furthermore, several natural analogue peptides exert an antagonistic function by inhibiting proliferative response of T cells specific to gp120 with a wild-type sequence. If similar events occur in vivo, they may represent an additional escape mechanism for HIV. In fact, antagonism for CD4 Th response may occur during superinfection with a different strain, or with the appearance of a variant carrying a mutated antagonistic sequence. In both cases, impaired Th cell function could lead to reduced immune control of HIV infection by interfering with CTL and antibody response.     

Enhanced cellular immune response and reduced CD8(+) lymphocyte apoptosis in acutely SIV-infected Rhesus macaques after short-term antiretroviral treatment

Losing the decisive virus-specific functions of both CD4(+) and CD8(+) T lymphocytes in the first weeks after immunodeficiency virus infection ultimately leads to AIDS. The SIV/rhesus monkey model for AIDS was used to demonstrate that a 4-week chemotherapeutic reduction of viral load during acute SIV infection of macaques allowed the development of a competent immune response able to control virus replication after discontinuation of treatment in two of five monkeys. Increasing SIV-specific CD4(+) T-helper-cell proliferation was found in all macaques several weeks after treatment, independent of their viral load. However, only macaques with low viral loads showed persistent T-cell reactivity of lymph node cells. In contrast to animals with higher viral loads, T-helper-cell counts and memory T-helper cells did not decline in the two macaques controlling viral replication. Lymphocyte apoptosis was consistently low in all treated macaques. In contrast, high CD8(+) lymphocyte death but only slightly increased CD4(+) lymphocyte apoptosis were observed during the first weeks after infection in untreated control animals, indicating that early apoptotic death of virus-specific CTL could be an important factor for disease development. Antiretroviral treatment early after infection obviously retained virus-specific and competent T lymphocytes, whereby a virus-specific immune response could develop in two animals able to control the viral replication after cessation of treatment.     

Lymphoid and extralymphoid CD4 T cells that orchestrate the antiviral immune response

This review summarizes the present understanding of the biology of CD4 T cells during both the acute and memory phases of the response to nonpersisting viral infection. Elucidating the precise role of CD4 T cells in viral infections has been a challenge due to characteristics intrinsic to the CD4 response and the slow development of tools that allow accurate identification of the virus-specific cells in vitro and in vivo. This is especially apparent in comparison with antiviral CD8 T cells, for which immunologists possess many tools for tracking the cells throughout a response. However, recent developments in technology to follow antigen-specific CD4 T cells in virus infections have improved our understanding greatly. Ex vivo technologies such as the enzyme-linked spot forming assays and more recently the FluoroSPOT assays, cytokine capture and the advent of class II major histocompatibility complex multimers have improved our ability to accurately enumerate the virus-specific CD4 T-cell response. The development of virus-primed T-cell receptor transgenic CD4 T cells and imaging technologies that take advantage of allotype marking and luciferase or fluorescent transgenes now allow for high-resolution tracking of virus-specific CD4 T cells in many tissues. Inspite of these new technologies, many questions remain regarding the dynamics of CD4 memory T-cell populations and their contribution to immune protection against viral infections.     

CD4+ NK cells can be productively infected with HIV, leading to downregulation of CD4 expression and changes in function

NK cells mediate the innate immune response, and HIV-infected individuals demonstrate altered NK cell phenotype and function. We find that CD4+ NK cells are susceptible to HIV infection; this could account for the NK cell dysfunction seen in HIV-infected individuals. CD4+ NK cells express CXCR4 and can be infected with X4-tropic viruses and some primary R5-utilizing viral isolates. Treatment with the CXCR4 ligands AMD3100 and SDF-1α partially blocks infection with X4-tropic virus, treatment with anti-CCL Igs upregulates CCR5 surface expression and enables infection with HIV-Bal. HIV infection of NK cells results in CD4 downregulation and the production of infectious virus. HIV-infected CD4+ NK cells mediate NK cell cytotoxicity, however, HIV infection is associated with decreased chemotaxis towards IL-16. Thus, HIV infection of CD4+ NK cells could account for the NK cell dysfunction observed in HIV-infected individuals. Furthermore infected NK cells could serve as a viral reservoir of HIV in vivo.