Research Article: Thirty Years with HIV Infection—Nonprogression Is Still Puzzling: Lessons to Be Learned from Controllers and Long-Term Nonprogressors

Date Published: May 27, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Julie C. Gaardbo, Hans J. Hartling, Jan Gerstoft, Susanne D. Nielsen.


In the early days of the HIV epidemic, it was observed that a minority of the infected patients did not progress to AIDS or death and maintained stable CD4+ cell counts. As the technique for measuring viral load became available it was evident that some of these nonprogressors in addition to preserved CD4+ cell counts had very low or even undetectable viral replication. They were therefore termed controllers, while those with viral replication were termed long-term nonprogressors (LTNPs). Genetics and virology play a role in nonprogression, but does not provide a full explanation. Therefore, host differences in the immunological response have been proposed. Moreover, the immunological response can be divided into an immune homeostasis resistant to HIV and an immune response leading to viral control. Thus, non-progression in LTNP and controllers may be due to different immunological mechanisms. Understanding the lack of disease progression and the different interactions between HIV and the immune system could ideally teach us how to develop a functional cure for HIV infection. Here we review immunological features of controllers and LTNP, highlighting differences and clinical implications.

Partial Text

Prior to the introduction of combination antiretroviral therapy (cART) it was observed that a minority of the individuals infected with Human Immunodeficiency Virus type 1 (HIV-1, from now on referred to as HIV) did not progress to Acquired Immunodeficiency Syndrome (AIDS) or death. This minority maintained normal CD4+ cell counts in the absence of treatment for several years—in some cases for more than two decades (reviewed in [1]) and therefore the terminology Long-Term Nonprogressors (LTNP) was proposed. When the technique for measuring the viral load was introduced it became evident that some of these patients, who did not clinically progress, had low or even nondetectable viral replication. This phenomenon leads to the additive definition of the non progressor-phenotype referred to as controllers due to their ability to control viral replication in the absence of cART. Today, non-progressors are a collective name for controllers and LTNP who are clinically similar. Except for certain demands for the duration of the infection in LTNP, they are only to be differentiated according to control or not of viral replication, respectively. Understanding the mechanism for the lack of disease progression in controllers and LNTP could ideally teach us how to develop a functional cure for HIV infection, and for this reason these subpopulations of HIV-infected patients have gained immense interest.

It is well-established that LTNP and controllers are different subpopulations [22–25], supporting the idea that different immunological mechanisms are responsible for the preserved CD4+ cell counts. LTNP and controllers are described as rare populations comprising few percentages of all HIV-infected individuals, and with little overlap between them [22–27], although the definition of the populations suffers from lack of consensus in terminology and inclusion criteria, impeding the comparison of findings.

The CD4+ cell count in a given patient at any time is the result of production, destruction, and traffic between blood and lymphatic tissue, and when the destruction exceeds the production the CD4+ cell count decreases. Thus, LTNP and controllers may have differences in production, destruction, or distribution of CD4+ cells compared to progressors in order to maintain a normal CD4+ cell count.

The understanding of the immune system is constantly changing as a consequence of rapidly expanding knowledge. Recently, the discovery of T-cell subsets with pro- and anti-inflammatory properties has altered our view on immunology. Regulatory T cells (Tregs) are anti-inflammatory T cells, while Th17 cells have proinflammatory properties. Tregs are crucial in sustaining tolerance to self-antigens [93, 94] and suppressing T-cell activation resulting in down-regulation of immune activation, including reduction in anti-tumor immunity, graft rejection, and graft versus host disease ([95], reviewed in [96]). Finally, the role of Tregs in chronic viral infections, including HIV, has gained considerable interest due to their immunosuppressive capabilities. Thus, in theory, Tregs can downregulate the chronic IA seen in HIV infection making Tregs a key element in the understanding of the interaction between the host immune system and HIV (reviewed in [97]). For this reason, Tregs have been suggested as downregulators of the unbeneficial unspecific IA in HIV-infection, expecting high levels of Tregs as being an advantage. However, levels of Tregs in HIV-infected, untreated, progressing patients have been shown to be elevated compared to healthy controls in a number of studies ([98–100] reviewed in [101]). This suggests that high levels of Tregs are actually harmful, possibly because they downregulate beneficial HIV-specific responses. In support of this, the level of Tregs in controllers has been reported to be lower compared to progressors, and closer to healthy controls, although conflicting results have been reported as well [70, 77, 102–106]. Furthermore, it has been shown that the suppressive activity of Tregs in EC is preserved, while it was found to be disrupted in progressors [105]. Finally, Tregs have been suggested to increase with age (reviewed in [107]), possibly contributing to the reported loss of non-progression in some individuals. All together this is supportive of a significant influence of Tregs on non-progression.

CD4+ cell depletion occurs in the blood as well as in the SLT of LN and gut-associated lymphatic tissue (GALT) where the majority of the CD4+ cells reside. During primary HIV infection a vast number of cells are depleted, reaching a loss of more than 50% in LN as chronic infection is established [119, 120]. It has been proposed that HIV damages the structures in the LT, that help sustain the normal CD4+ cell population replacing the functional space with collagen. Thus, the greater the amount of the collagen deposition, the lower the CD4+ cell count and the smaller the number of naive CD4+ cells [121]. Also, LN biopsies from HIV- and SIV-infected individuals show breakdown of the lymph node architecture and evidence of apoptosis [122]. In contrast, a preserved lymph-node architecture was reported in the history of HIV in non-progressors compared to progressors, indicating that progressors host a preserved SLT [123]. GALT is the main defence against infectious microorganisms in the gastrointestinal (GI) tract and consists largely of T cells. Importantly, the main part of Th17 cells reside in the GALT [124]. Th17 cells are important for the integrity of the gut mucosal barrier by stimulating epithelial proliferation and inducing a proinflammatory environment by recruiting neutrophils to fight microorganisms. Upon acute HIV infection follows a significant depletion of CD4+ cells in the GALT [125, 126]. The depletion is linked to a damage of the mucosal barrier that may be due to an imbalance of Th17 cells as the massive depletion of CD4+ cells during acute HIV and SIV infection in particular includes Th17 cells [125, 126]. The damage to the mucosal barrier results in microbial translocation (MT)—a continuing leak of microbial remnants from the GI tract that enters the systemic circulation. These microbial products lead to immune activation [111, 127, 128], thereby contributing to HIV progression. The data on mucosal integrity and the influence of MT on immune activation in non-progressors are limited. One study using a rhesus macaque model has shown that spontaneous restoration of mucosal CD4+ cells upon acute SIV infection is predictive of non-progression [129]. Furthermore, EC and VC present with similar preserved numbers of CD4+ cells in rectal biopsies comparable to HIV-negative individuals, while the number in progressors is reported to be diminished [130, 131]. However, the level of lipopolysaccharide (LPS) used as a marker of MT is comparable in controllers and progressors and elevated compared to HIV-negative individuals [73], indicating that low chronic immune activation in non-progressors might have effect in the long-term despite the appearance of the relatively intact mucosal barrier. Thus, present data indicate that non-progressors are distinct from progressors in several aspects of the integrity of the mucosal barrier and MT, suggesting an important mechanism for the capability of non-progressors to control immune activation and HIV infection. However, to determine the causal relationship between MT and control of HIV infection prospective studies are needed.

HIV-specific CD8+ and CD4+ cells and neutralizing antibodies are considered an important albeit most often insufficient element in suppressing viral replication (reviewed in [132, 133]). Some of the first studies were made of HIV-infected patients with primary infection. Here it was shown that the level of HIV-specific CD8+ cells paralleled the efficiency of control of primary viremia. Also, patients who mounted strong gp160-specific CD8+ cell responses showed rapid reduction of acute plasma viremia, while viremia in patients with low virus specific CD8+ cell activity was poorly controlled [134]. Another study showed that an absent HIV-specific CD8+ cell response during primary HIV infection was associated with prolonged symptoms, persistent viremia, and low CD4+ T-cell count [135]. Furthermore, it has been shown that in vivo depletion of CD8+ cells eliminates the ability to contain SIV replication [136]. For this reason an HIV-specific CD8+ cell immune response is widely accepted as a contributor to control of viral replication and lack of progression in non-progressors, and this has been evaluated in a number of studies. Thus, it has been shown that non-progressors are able to maintain an established CD8+ cell precursor pool and present with a consistent highly functional HIV-specific response, while this ability is lost in progressors [137, 138]. Also, the capacity of virus-specific CD8+ cells to proliferate in response to stimulation with HIV antigens is reported to be preserved only in non-progressors [139]. This is in agreement with findings from a prospective study of an increase in polyfunctionality in HIV-specific CD8+ cell responses from EC, and a decrease in progressors over time [140], and with findings of a stronger and broader cytokine and chemokine response following HIV-specific stimulation of PBMC from EC compared to progressors [70, 77]. In addition, it has been reported that the inhibitory immunoregulatory receptor CTLA-4 is selectively upregulated in HIV-specific CD4+ cells in progressors compared to non-progressors. CTLA-4 expression was also found to be positive associated with disease progression and negatively associated with the capacity of CD4+ cells to produce IL-2 in response to viral antigen [141]. Furthermore, it has been shown that in non-progressors HIV-specific CD8+ T cells efficiently eliminate primary autologous HIV-infected CD4+ cells [142]. Additionally, it seems of importance if the HIV-specific cells are activated or not, as it has been shown that ECs possess lower levels of activated HIV-specific CD8+ cells and of recently divided HIV-specific CD4+ cells than progressors [70]. Based on these data an ideal HIV vaccine would induce strong HIV-specific immune responses and minimize HIV-specific immune activation. Another goal of vaccine development is induction of antibodies that neutralize a broad range of HIV isolates. Although antibodies can be elicited by HIV infection, those that are broadly neutralizing are undetectable in most individuals (reviewed in [143]). The level and the breadth of neutralizing antibodies are reported to correlate to viral load [144, 145], and the same or lower levels of antibodies are reported in controllers compared to progressors [144, 146]. Furthermore, one study showed that no single anti-HIV antibody specificity was a clear correlate of immunity in controllers [146]. This is consistent with neutralizing antibodies as poor contributors to non-progression. Contrary, antibodies directed against autologous Env variants are reported to be present in non-progressors [147], and efficient elicitation of de novo neutralizing antibodies has been shown in SIV controllers [148].

Despite effective cART complete eradication of HIV seems unlikely, and complete eradication of HIV is so far only obtained once in the Berlin-patient [30]. In general, low-level HIV replication continues despite cART. This is in part due to the capability of HIV to conceal itself and persist in cellular reservoirs. Furthermore, a major impediment to the eradication of HIV is latently infected resting CD4+ cells that are characterized by proviral DNA integration into the host genome; particulary memory CD4+ cells have proven to be a major cellular reservoir for HIV [151]. The major anatomical site for HIV reservoir is SLT including GALT [152–154]. Thus, viral reservoirs are considered a major obstacle to eradicate HIV and considered to be the reason for rebound viraemia during cART interruptions. Notably, the concept of a functional cure has emerged where lifelong control of viral replication is obtained and disease progression is avoided although provirus is detectable. This might be illustrated by the viral control found EC.

A common feature in non-progressors is preserved immunology. However, reports of loss of the non-progressor status with declining CD4+ cell counts in LTNP have been observed, and these patients may eventually require cART. Likewise, a loss of viral control in controllers is reported. Interestingly, progression and AIDS events in controllers despite low or undetectable viral loads events are reported as well [2, 8, 22, 29, 39, 48, 73, 160]. As a result of this, cART has been suggested to controllers.

Rare groups of HIV-infected patients that do not progress to AIDS or death have been known since the beginning of the HIV epidemic. Some of these non-progressors control viral replication, that is, the controllers, while LTNP, have ongoing viral replication. So far, it is not clear why these patients do not progress, but immunological mechanisms have been suggested. The immunological response to HIV infection can be divided into an immune homeostasis resistant to HIV and an immune response leading to viral control. This paper has focused on immunology in non-progressors. We suggest that two different mechanisms are responsible for preserved CD4+ cell counts in controllers and LTNP.




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