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HIV pathogenesis: 25 years of progress and persistent challenges

2008; Lippincott Williams & Wilkins; Volume: 23; Issue: 2 Linguagem: Inglês

10.1097/qad.0b013e3283217f9f

1473-5571

Jay A. Levy,

Pneumocystis jirovecii pneumonia detection and treatment

Introduction In 1981, a new disease syndrome appeared in human populations in the United States and elsewhere characterized by a deficiency in the immune system [1]. Patients presented with unusual infections and cancers such as Pneumocystis jiroveci (carinii) pneumonia and Kaposi's sarcoma. This acquired immune deficiency syndrome (AIDS) consisted of a marked reduction in CD4+ cell numbers and enhanced B-cell proliferation and hypergammaglobulinemia. This latter finding most likely reflects immune activation, which has recently been reappreciated as a major cause of the pathogenic pathway. In this regard, chronic inflammation has received better attention as a cause of cancer, cardiovascular diseases, and other comorbidities appearing in long-term HIV-infected people. Two years after the recognition of AIDS, the causative agent, a human retrovirus in the lentivirus family, was identified [2–4]. Early observations had indicated this virus was spread through intimate sexual contact (e.g., genital fluids), blood and blood products, and through mother-to-child transmission [5]. Although those three means of transmission have not changed, great progress has been achieved in preventing mother-to-child transmission with antiviral drugs and HIV infection from contaminated transfused blood and blood products. The discovery of HIV led rapidly to its cloning and the identification of its genes, as well as efforts to find treatment and prevention, particularly through a vaccine. Within the past 10 years, effective antiviral therapies have become available directed at the major enzymes of the virus (reverse transcriptase, protease, and integrase) as well as its attachment and fusion sites [6]. These drugs offer great hope to those at risk of advancing to AIDS, and their availability in resource-limited countries remains an important priority. Long-term therapy, however, may not be possible because of toxic drug side effects and drug resistance [6]. Other treatments are needed, and a cure of HIV infection, if at all possible, is a major challenge. Importantly, the successful development of an effective vaccine would have the most long-ranging effects on the epidemic. This review will highlight the background and progress made over the past 25 years in understanding many aspects of HIV pathogenesis. This field has been extensively reviewed in a recent monograph [7], so only brief summaries of some topics will be given. Particular attention is placed on findings reported most recently that continue to contribute to our knowledge of HIV and its pathogenic course. Several challenges still facing the field are discussed. HIV characteristics Genetic differences Since the discovery of HIV, epidemiological and genetic studies have indicated that the AIDS viruses, HIV-1 and HIV-2, consist of different virus groupings. Variations primarily in the envelope genes help distinguish them. The virus groups differ by at least 30% whereas the clades (subtypes) differ by 15–20%. Only HIV-1 has subtypes or clades of which nine have been recognized (A–D; F–H; J–K). The original clades E and I have been identified as recombinant viruses [8–10], and clade G may also fit best into this category [11]. Of the three main groups of HIV-1, M, N, and O, the majority of infections occur with group M; about 100 000 infections have occurred with group O. Very few infections have taken place with group N. HIV-2, discovered about 2 years after HIV-1 [12], differs by 40% and consists of eight different groups of which A and B are the most prominent. These HIV-1 and HIV-2 groups and HIV-1 subtypes are now distributed throughout the world; all are found in Africa [13]. HIV-1 clade C is becoming the most prevalent transmitted virus. Its wide transmissibility could reflect the high viremia set point in clade C infections and the higher virus levels found in genital fluids than found with other clades [14]. Moreover clade C viruses have three NFκB sites in comparison to one to two in other clades [15]. During immune activation, the NFκB sites make HIV more responsive to cytokines such as TNF-α that enhance virus production. An important finding in the last decade has been the emergence of recombinant viruses forming in several regions of the virus between HIV clades and groups (Fig. 1). Recombination between HIV-1 and HIV-2 has not been reported and probably cannot form because of differences in the location of the RNA dimer hairpin sites [16]. Virus recombinations can occur particularly after coinfection or superinfection of cells by two or more viruses prior to the establishment of a chronic infection. In the latter case, the downmodulation of the CD4 molecule would create a resistant state. Superinfection is common in viral infections [17], and, thus, its occurrence in HIV is not surprising and has been reported even in long-term healthy individuals [18]. Obviously, control of multiple HIV infections within an individual is possible. Nevertheless, this process can lead to recombinant viruses resistant to certain drugs and immune responses [19]. Thus far, superinfection is being detected more often during the early stages of HIV infection than in chronic infection [20].Fig. 1: Recombinant virus CRF 18_cpx. This circulating recombinant form 18 is a complex (cpx) virus which contains genetic regions derived from 7 different HIV-1 clades (subtypes); U, indicates an unknown subtype. Figure provided by Rafael Najera.General properties HIV-1 and HIV-2 are retroviruses with both structural and accessory genes. The latter determine the extent of their replicative and pathogenic characteristics that vary among HIV-1 groups and clades. For example, group M clades appear to replicate 100-fold better than group O or HIV-2 isolates [21]. In addition, clade A virus infections have a slower disease course than infections with other clades [22]. HIV-2 has a lower transmission rate and a less pathogenic course resembling, in part, the asymptomatic infection of the simian immunodeficiency virus (SIV) in sooty mangabeys and African Green Monkeys (AGMs) [23]. These observations most likely reflect less immune activation (see below). Moreover, HIV-2 has lower progeny virus production and thus less infectious virus in body fluids [24]. Comparison of the biologic and genetic properties of viruses from the same individual has suggested independent evolution in distinct compartments; for example, blood, lymphoid tissue, oral cavity, central nervous system, genital fluids, and gastrointestinal tract [25–27]. This viral heterogeneity is now more easily defined through novel innovative technologies for genome sequencing, such as detecting single nucleotide polymorphisms (SNPs) through pyrosequencing [28] and other procedures. Cell tropism The initially observed HIV macrophage-tropism and T-cell line-tropism are determined primarily by the coreceptor used along with CD4 for virus attachment to cells. Macrophage-tropic viruses utilize the chemokine receptor, CCR5, and are known as R5 viruses. Viruses infecting established T-cell lines use the CXCR4 receptor and are known as X4 viruses [29]. These latter viruses are generally more cytopathic than R5 viruses and were initially called syncytium-inducing in contrast to the non-syncytium-inducing R5 viruses [30]. Individuals who lack CCR5 expression are resistant to R5 virus infection but are susceptible to X4 viruses (see below). A large number of other chemokine coreceptors can also act as primary or secondary attachment sites for both HIV-1 and HIV-2 isolates (e.g., CCR3, CCR2b) but are not commonly involved in infection [24,29,31]. In addition, besides CD4, galactosyl ceramide (GalC) can serve as a major binding site for HIV-1 infection in the bowel, vagina, and brain [32–34]. Moreover, HIV complexed with antibodies can gain entry into T cells and macrophages and other cells through Fc and complement receptors [35,36]. Over the past 10 years, a variety of additional cellular binding proteins have been found associated with HIV infection. Among these, the most common are the C type lectins, particularly DC-SIGN, as well as the leukocyte function-associated antigens (LFAs) and the intercellular adhesion molecules (ICAMs) [37,38]. Most recently, the α4β7 integrin has been identified as an HIV-binding site particularly on CD4+ memory T cells [39] – a possible explanation for the loss of these cells in the gastrointestinal tract during early infection. (See below). HIV infection HIV transmission Transmission of HIV is dependent on the biologic properties of the virus, its concentration in the exposed body fluid, and the nature of the host susceptibility both at the cellular and immunological levels. In this regard, a recent study has suggested that the initial infection by HIV occurs in most patients by a single virus [40]. If confirmed, this low level of virus transmission offers a 'window of opportunity' to prevent transmission using a drug or vaccine. Importantly, with transmission of most viral infections, a free virus is involved. In the case of HIV, integration of the virus into the cellular chromosome establishes virus-infected cells as sources of transmission [41]. They can transfer HIV to cells of both the immune system (e.g., T cells, macrophages, dendritic cells) as well as mucosal cells lining the vaginal and anal canals [42,43] (Fig. 2). The transmission of HIV is associated with large amounts of virus in the genital fluids, which are often found (but not always) with high plasma viral loads [44]. These findings are most common with advanced disease and during acute infection when the risk of transmission can be increased over 20-fold [45].Fig. 2: HIV-infected macrophage interacting with epithelial cells derived from the cervix. Tiny circles in the intercellular space are viruses. Figure provided by David Phillips; reproduced with permission from [7].Sexually transmitted diseases increase both infectious virus and infected cells in genital fluids and can enhance HIV transmission [46]. The lack of circumcision has been linked to an increased risk of infection for males [47], and transmission has been reduced by circumcision of male adults [48]. This observation can be explained by the large number of HIV-susceptible dendritic cells in the foreskin [49]. Moreover, inflammation often found with the prepuce provides more target cells for infection by HIV encountered through the vaginal, anal, and oral routes. Studies using SIV suggest that the cervix is the first tissue infected after intravaginal virus inoculation [50]. Within 2 days, the cervix is infected and the virus then spreads most likely through dendritic cell (and CD4+ cell) migration to regional lymph nodes and subsequently into the blood stream. Passage of virus-infected cells in semen through the cervical os into the uterus would appear to be a major route of transmission to women. For this reason, diaphragms were evaluated as a preventative measure but were used in the trials most often in addition to male condoms [51]. Thus, their independent value could not be evaluated. Some infected people have been identified as super-producers of virus in seminal fluids [52]. In certain cases, the presence of specific amyloid fibrils in semen may enhance the rate of HIV transmission by increasing virus attachment to cells [53]. Early virus–host cell interactions HIV infection results first from virus attachment to a major receptor and then generally further binding through coreceptors and other adhesion molecules. Subsequently, virus–cell fusion takes place, most likely between the virus gp41 and a fusion receptor on the cell, perhaps a glycolipid. This interaction permits the HIV capsid to enter the cell. Reverse transcription and integration then take place primarily in cells that are activated [54]. These HIV-infected cells become persistent reservoirs for the virus and sources of transmission. During early infection, the induction of chemokines can bring more target cells to the site of infection and inflammation [55]. Thus, these cellular products can increase virus spread rather than prevent it by their antiviral activity [56]. Observations over the past 25 years have indicated that many cells in the body (e.g., brain, bowel, kidney, prostate) can be infected by HIV besides cells of the immune system [7]. Thus, attempts to cure HIV infection must consider all of its cellular reservoirs. Importantly, HIV has been shown to integrate into resting CD4+ T cells, even at a low virus input [57]. This finding could explain the detection of integrated HIV in immunologically naive CD4+ T cells [58]. Virus infection can be blocked at entry, prior to reverse transcription, after reverse transcription, or after integration into an infected cell. In the latter case, latency or a silent infection can result. (See below). Virus integration and established infection does not take place unless the cell is activated within a few days after virus entry [54]. Presence of virus subtypes during HIV infection Several studies have indicated that R5 viruses are generally first observed in the blood during acute or early infection [59]. Later, in association with disease, the more cytopathic X4 virus emerges. In about 50% of AIDS cases, an R5 virus is found though it shows biologic properties associated with virulence in the host [60]. It replicates more rapidly, produces high amounts of progeny virus, and induces cytopathology. Some studies suggest that the initial infecting R5 virus often evolves into a dual-tropic R5/X4 virus and then to an X4 virus [61]. Specific genetic alterations in the envelope regions of the infecting R5 virus have been shown to be responsible for the change in coreceptor usage [62]. Alternatively, the early R5 virus infection may be followed by an X4 virus infection resulting from the reemergence of a related X4 virus that coinfected the individual at the time of initial transmission. The processes influencing these events, which include a compromise to the immune response, have not yet been fully defined [7]. The reasons suggested for R5 virus predominance during acute and primary infection include the following: R5 viruses have many susceptible CCR5+ CD4+ T-cell targets during immune activation; R5 viruses can more readily infect nonactivated cells; R5 viruses can infect macrophages and dendritic cells; higher R5 progeny virus production takes place in infected cells; R5 viruses preferentially infect CCR5-expressing CD4+ cells in the gastrointestinal tract; R5 viruses are less recognized by the immune system [e.g., cytotoxic T-lymphocytes (CTL)]. Chronic and late HIV infection About 6 months after the acute infection phase, most infected individuals enter into an asymptomatic period in which virus levels in the blood reach a set point often below 20 000 RNA copies/ml. This event reflects primarily the antiviral responses of the innate and adaptive immune systems. (See below). Circulating innate factors such as mannose-binding lectins (MBLs) and complement could be involved. Anti-HIV antibodies, as well as natural killer (NK) and T cells, play important roles. In some infected individuals, an absence of detectable viremia indicates efficient HIV control; this unusual group has been termed 'elite controllers' [63]. HIV replication during the subsequent persistent infection period can take place at low levels in the lymph nodes and other tissues and appears to reflect the extent of control by antiviral immune responses. After 10 years of infection, about 50% of the individuals without therapy will begin to develop signs of the infection including a decrease in CD4+ T-cell counts below 350 cells/μl [64] and loss of immune activities (specifically HIV-specific CD4+ and CD8+ T-cell responses). Viral destruction of lymphoid tissue mirrors this progression of HIV infection [65]. As noted above, the virus at this time can have an X4 phenotype or be a R5 virus with virulence properties. In industrialized countries, infected individuals are treated with anti-HIV drugs once the persistent period goes into this symptomatic phase. Latency In some cases, HIV infection can result in a silent infection showing no evidence of virus progeny production. This HIV latency can involve the site of virus integration, its state after integration (e.g., methylation), and the absence of sufficient viral Tat or Rev expression [58]. In addition, a variety of cellular proteins such as histone deacetylase (HDAC), YY1, and the CD8+ antiviral factor can lead to a suppression of virus infection in the infected cell [66–68]. Importantly, cellular intrinsic antiviral factors can be involved (Section 'Intrinsic intracellular factors'). Attempts to activate HIV from latent reservoirs with a variety of compounds have not shown beneficial clinical results, though these compounds may induce HIV replication in vitro[69]. What factors influence the HIV pathogenic course CD4+ cell loss Destruction of CD4+ T cells is a primary reason for the opportunistic infections and cancers associated with HIV infection. Many factors can be involved in this CD4+ cell loss (Table 1).Table 1: Potential factors involved in HIV-induced loss of CD4+ lymphocyte number and function.For example certain cytokines (e.g., TNF-α) and HIV proteins (e.g., Tat, Nef, Vpr, Vpu) can influence the extent of HIV replication and CD4+ cell death. Other processes involved in this CD4+ cell loss can include the conventional disruption in metabolic processes and cell membrane integrity by HIV causing necrosis. In many cases, apoptosis results from direct virus infection or an indirect effect of immune activation (see below). More recently, autophagy has been noted as a possible cause of bystander CD4+ cell death with HIV infection [70]. Another reason can be CD8+ cytotoxic T-cell (CTL) activity against normal CD4+ cells [71]. The reduction in the peripheral blood CD4+ cell count over time also results from a block in T-cell restoration processes in the thymus [72]. A major effect of acute HIV infection is the widespread destruction of memory CD4+ cells in the gastrointestinal tract [73]. These T cells in the mucosal-associated lymphoid tissue (MALT) can induce the overall immune responses of the host. In addition, an interruption in the integrity of the gastrointestinal epithelium permitting bacteria to enter the blood can cause inflammation and activation that encourage further CD4+ cell loss [74]. To what extent this latter process contributes to pathogenesis is actively under study. Immune activation Probably the most important concept that has reemerged as an important component of HIV pathogenesis is chronic immune activation [75–78]. Hyperimmune responses with production of pro-inflammatory cytokines such as TNF-α can lead to enhanced HIV production and loss of CD4+ and CD8+ T cells through apoptosis [79] and other processes including perhaps immune senescence [80]. The absence of this chronic activation in long-term survivors (though probably reflecting the low viremia) and importantly in natural nonpathogenic SIV infection models with high viral loads (e.g., sooty mangabey) support this conclusion [81,82]. In this regard, the pro-inflammatory cytokine, IL-17, associated with the CD4+ T-cell subset, TH-17, may be important in HIV infection. These cells help combat bacterial and fungal infections and have been found reduced in the gastrointestinal tract of HIV-infected patients but not nonpathogenic SIV infections [83]. Whether these cells are also participants in immune activation merits further study. Most recently, the production of IFN-α by plasmacytoid dendritic cells (PDCs) has been cited as contributing to immune activation [84]. PDCs isolated from sooty mangabeys with chronic SIV infection show low IFN-α production in vitro, in association with reduced immune activation [85]. Other factors that may explain this observation in natural SIV-infected hosts include activation of Tregs, upregulation of PD-1 expression, lack of microbial translocation, and downmodulation of the TCR-CD3 complex by Nef [82]. Obviously, factors inducing vs. reducing immune responses and the time of this expression must influence the clinical course (see Conclusions). Cofactors in HIV pathogenesis Microbial infections can enhance (e.g., herpesvirus) or delay (e.g., GB virus C) HIV pathogenesis [86]. Importantly, certain polymorphisms in the human histocompatibility locus can affect the strength of the cellular immune anti-HIV responses [87] (Table 2).Table 2: HLA association with HIV disease progression.Other genetic differences shown to influence disease progression include the relative expression of the chemokine receptors (e.g., CCR5), chemokines, and other cytokines (Table 3) (refer http://www.hiv-pharmacogenomics.org). Moreover, homozygosity for variant MBL2 alleles has been associated with an increased risk of HIV infection and progression to AIDS [88,89]. A reduction in the level of this innate antiviral protein or its altered structure or both seems involved [89]. Most recently, apolipoprotein E4 has been implicated in accelerating HIV-related disease [90].Table 3: Cellular genes that affect HIV disease progression.Intrinsic intracellular factors The importance of natural intracellular anti-HIV resistance factors has recently been highlighted. APOBEC3G (and 3F), a cytosine deaminase, alters single-stranded DNA synthesis during reverse transcription [91]; it causes the production of an inactive DNA product that is degraded by the cell. The viral protein Vif interacts directly with APOBEC3G (and 3F) and prevents its activity by blocking the incorporation of APOBEC into viral particles [91,92]. Other processes may also be involved. Recent studies have suggested that a higher expression of APOBEC3G and 3F within the cell is associated with lower viral replication during acute infection [93]. Moreover, these cellular proteins could be responsible for the resistance or latent infection of resting CD4+ cells [94]. Another intracellular factor, TRIM5α, regulates the ability of certain retroviruses to infect human cells and for HIV to infect monkey cells. This gene appears to interact with the viral capsid and prevent uncoating [95]. Other activities such as reverse transcription may also be blocked. This last year, HIV Vpu has been shown to prevent the activities of a human cellular membrane protein, tetherin [96], and a calcium-modulating cyclophilin ligand [97] that block budding of the virus particle from the cell surface. Moreover, host genome-wide screening has suggested many other intracellular proteins needed for HIV replication that could be targets for anti-HIV therapy [98–100]. Host anti-HIV immune responses General comments The host immune response consisting of humoral and cellular components of innate and adaptive immunity greatly determines the clinical course. The key difference between these two major immune systems is the quick response of the innate system to an incoming pathogen; a microorganism can be recognized in minutes to hours against days to weeks observed with the adaptive immune system. Innate immunity responds to a conformational pattern of a pathogen rather than a specific epitope [101]. Humoral immunity Innate immune responses MBLs and complement, that can readily inactivate virus, are important soluble anti-HIV innate immune factors [88,89,102,103]. Moreover, other circulating proteins can block HIV infection [104,105]. Naturally occurring anti-Tat IgM antibodies can inhibit the effects of Tat [106], and naturally occurring IgM antileukocyte autoantibodies [107] could prevent HIV entry into cells. Anti-HIV antibodies Neutralizing antibodies against the HIV envelope gp120 and gp41 can have great importance as adaptive immune responses. In some situations, antibodies to cell surface proteins [e.g., LFA, ICAM, human leukocyte antigen (HLA)] can mediate this activity [108,109]. Genetic and nongenetic factors have been shown to influence this sensitivity to neutralization including linear and conformational epitopes as well as the degree of envelope glycosylation and stability. Some antibodies may interact with a cluster of oligomannose glycans on gp120, suggesting another direction for vaccine development [110]. Several monoclonal antibodies have been derived from human sera that react with gp120 or gp41 and have broad anti-HIV reactivity. This observation indicates that this objective can be achieved. These antibodies recognize a consensus sequence (or carbohydrate moiety) shared by a variety of different HIV-1 and HIV-2 groups or clades [111]. More recently, a neutralization epitope has been revealed on gp120 after an interaction with CD4. This approach could be used to develop immunogens that will direct antibodies to that region in gp120, now called CD4-induced or CD4i antibodies [112,113]. Antibodies that attach to virus-infected cells (via gp120 or gp41) can also be important in direct killing of infected cells by antibody-directed cellular cytotoxicity (ADCC). This process, mediated through the Fc receptor primarily by NK cells, is found in healthy infected individuals and correlates with a clinically healthy course [114]. Enhancing antibodies and autoantibodies At the same time that neutralization of HIV is an important parameter of protection, antibodies that attach with less affinity to the virus need to be appreciated. They can facilitate HIV infection of T cells, macrophages, and other cells through the Fc or the complement receptor [35,36]. This antibody-mediated enhancement of HIV infection can be associated with development of disease [115]. Circulating autoantibodies to hematopoietic cells, such as red cells, neutrophils, and CD4+ cells, may also contribute to HIV pathogenesis [116]. Cellular immunity Dendritic cells Dendritic cells play a role in both innate and adaptive immune activities in HIV infection. They are antigen-presenting cells (APCs) for T and B cells and produce cytokines that influence the immune response [117]. Various dendritic cell types are found throughout the body [118]. Blood dendritic cells consist of PDCs and myeloid dendritic cells (MDCs). The MDC is the major APC in the blood. The PDC, a CD4+ lineage negative cell, is a precursor dendritic cell that can direct type 1 or type 2 immune response in a type 1 and type 2 manner [119]. It is found in lymphoid tissue in the CD4+ cell region and at low numbers in the blood (2–8 cells/μl). This cell is the major producer of type-1 interferons (IFNs) after exposure to viruses and other pathogens [120]. It expresses the chemokine coreceptors and can be infected by HIV but at low sensitivity [121]. Reduced PDC number is associated with the development of AIDS [122]. Notably, long-term survivors (see below) have higher levels of this cell type than even healthy controls [122]. Moreover, in acute HIV infection, the PDC number is inversely related to the viral load [123]. Those acutely infected individuals with a low viral load and high PDC could become long-term survivors. These findings support the conclusion that PDC and IFN are beneficial in HIV infection. Nevertheless, other studies indicate that early viremia can lead to an increase in PDC and IFN production that can cause enhanced and chronic immune activation [84,124]. Thus, the relative beneficial vs. detrimental roles of PDC and IFN need to be considered (see Conclusions). Other innate immune cells NK cells have an important function in destroying HIV-infected cells and are influenced by the production of cytokines such as IFNs and IL-12. They kill infected cells that lack major histocompatability class (MHC) I expression. The interaction of NK-inhibiting receptors (KIRs) on NK cells with certain HLA moieties can prevent this activity. The enhanced expression of KIRs, in the presence of HIV viremia, can suppress NK cell function [125]. Nevertheless, a beneficial clinical course has been associated with NK KIR 3DL1 and its BW4-801 ligand [126]. Other innate cells receiving attention in HIV infection are NKT [127] and γδT cells [128], but their clinical relevance in HIV pathogenesis has not been well-defined. CD4+ T lymphocytes CD4+ T cells, through cytokine production, have a major role in helping the immune response of B cells and other T cells. Some CD4+ cells can have a cytotoxic activity [129]. CD4+ T-cell help is particularly important for the efficient function of CD8+ T-cell immunity. Although CD4+ cells have conveniently been divided into TH1 and TH2 subsets, depending on the cytokines they produce, the polyfunctionality of CD4+ T cells (and CD8+ T cells) is more clinically relevant [87]. T-cell coproduction of IL-2 and IFN-γ appears to be beneficial for anti-HIV immunity [87,130]. The interaction of CD4+ cells with dendritic cells plays an important role in determining their production of specific cytokines. Strong HIV-specific CD4+ cell responses alone and particularly in association with HIV-specific CD8+ cells provide a good prognosis for the clinical course [131,132]. CD8+ T lymphocytes Noncytotoxic activity: Simillar to dendritic cells, CD8+ cells can function in both the innate and adaptive immune systems. A CD8+ cell noncytotoxic antiviral response (CNAR), mediated by a novel as yet unidentified CD8+ cell antiviral factor (CAF), blocks virus transcription without killing the infected cell [67]. CNAR/CAF appears to be an innate immune activity [67] that differs therefore from the conventional adaptive cytotoxic CD8+ CTL antiviral response that kills HIV-infected cells expressing specific viral epitopes. CNAR is found highest in long-term survivors (LTS); when this activity decreases, virus replication resumes with progression to disease [67]. This new type of cellular noncytotoxic antiviral response has since been observed in SIV and FIV infections as well as several other viral infections, including