CHAPTER 1 INTRODUCTION
1.6 Factors influencing the rate of disease progression
1.6.3 Viral and host factors
Several host genetic and immune factors as well as viral genetic factors may influence the rate of HIV-1 disease progression [79, 129, 132, 138-140]. For example, individuals who are homozygous for a 32-bp deletion in the CCR5 co-receptor gene show almost complete protection against HIV-1 acquisition (since the transmitted virus is highly dependent on this co-receptor for cell entry), and those who are heterozygous for the deletion or have polymorphisms that decrease CCR5 expression have delayed progression to AIDS [129, 141]. Polymorphisms in the CypA (Section 1.3.3) and Tsg101 (Section 1.3.8) host genes involved in HIV-1 replication have also been associated with differences in susceptibility to HIV-1 infection or in the rate of progression to AIDS [129, 142]. However, the majority of host genetic factors linked to altered disease progression mediate their effect through
influencing host immune responses to HIV-1. Similarly most viral genetic factors associated with slower or faster rates of disease progression are themselves consequences of host immune responses and/or affect pathogenesis through altering the effectiveness of host immune responses. Therefore the host and viral factors influencing HIV-1 disease progression will be discussed in terms of the innate, humoral and cell-mediated immune responses.
1.6.3.1 Innate immune responses
LTNPs maintain higher levels of dendritic cells [131], which play an important role in the innate immune response (Section 1.4.4.1.1). Dendritic cells produce IFN -α (Section 1.4.4.1.1) and two single-nucleotide polymorphisms (SNPs) in the IFN-α receptor have been associated with susceptibility to HIV-1 infection [143]. Polymorphisms in restriction genes upregulated by IFN-α and other type 1 IFNs, namely TRIM5α and APOBEC3G, have been linked to altered disease progression [144, 145]. However, it appears that polymorphisms in identified restriction factors are not the cause of viral control in the majority of elite controllers [131].
Increased NK cell activity has been detected in exposed but seronegative individuals [146]
and factors influencing NK cell activity have also been linked to altered disease progression.
A SNP in the HLA-C promoter gene has been identified as a major genetic determinant associated with lower viral set point, and may mediate its effect through influencing interactions with NK or CD8+ T cells leading to more efficient cell lysis [147]. However, this SNP does not explain elite control in the majority of elite controllers [131, 148]. The expression of the activating KIR3DS1 (on NK cells) in combination with HLA-Bw4
35 molecule ligands (including HLA-B*57 and HLA-B*27) is associated with slower progression to AIDS [149], and is overexpressed in LTNPs but not elite controllers [131].
Long-term non-progression in blood transfusion recipients of a Nef-deleted virus [150, 151]
may be partly accounted for by lack of Nef-mediated downregulation of HLA, which antagonises both NK cell and CD8+ T cell immune responses (Sections 1.4.4.1.3 and 1.4.4.3.1), although viral attenuation could also be a contributing factor (Section 1.6.5).
However, the majority of elite controllers do not harbour viruses with gross genetic defects such as Nef-deletions [152].
1.6.3.2 Humoral immune responses
There is not much data to suggest that antibody responses determine control of HIV-1 replication, although there is more evidence that they may be important in preventing infection [93, 131, 132]. In a macaque-SIV/HIV model, passively administered antibodies can protect against infection and disruption of ADCC activity dramatically increases susceptibility to SIV/HIV chimera infection [153]. Further, the modest protection against HIV-1 acquisition by the RV144 vaccine may have been elicited by non-neutralising antibodies [93] (Section 1.5.2). Mucosal immunoglobulin A (IgA) antibodies capable of neutralisation were also identified in exposed but seronegative individuals [146].
It has been shown that ADCC activity is more potent in elite controllers than in progressors [93]. However, since equally potent ADCC activity was shown in some acutely infected individuals and individuals on ART, potency may be a consequence rather than cause of level of viremia [93]. Broadly neutralising antibodies are less common in aviremic LTNPs [154] and elite controllers have lower titres of broadly neutralising antibodies and similar
levels of autologous neutralising antibodies when compared with progressors [155, 156].
Collectively these data suggest that neither ADCC nor neutralising antibodies play a major role in maintaining viremic control in HIV-1 controllers.
1.6.3.3 Cell-mediated immune responses
1.6.3.3.1 CD4+ T cell responses
HIV-specific CD4+ T cell responses of elite controllers and LTNPs have a higher proliferative potential than those of progressors, and also result in the secretion of multiple cytokines, including IL-2, upon stimulation, while CD4+ T cells from progressors mostly secrete IFN-γ [90, 131, 157]. Further, there are preserved central memory and activated effector memory CD4+ T cell subsets in HIV-1 controllers [158]. The preservation of a vigorous CD4+ T cell response in HIV-1 controllers may be important for CD8+ T cell- mediated control of virus replication, but whether or not it is crucial is unknown [82].
However, a recent study has shown that IL-21-secreting CD4+ T cells (preserved in elite controllers) may contribute to viral control through enhancing CD8+ T cell function [159].
It is also unclear whether preserved CD4+ T cell responses in controllers are a cause or consequence of low viremia and there is conflicting data in this regard [82, 90, 131]. It is clear at least that the proliferative capacity of HIV-specific CD4+ T cells can be restored by ART to levels observed in LTNPs, suggesting that this characteristic is influenced by the level of viremia [90, 160].
1.6.3.3.2 CD8+ T cell responses
As with HIV-specific CD4+ T cell responses, there are qualitative differences in HIV- specific CD8+ T cell responses between elite or viremic controllers and progressors. HIV-
37 specific CD8+ T cells from elite controllers and/or LTNPs are polyfunctional (secreting multiple cytokines) [161], have a high proliferative capacity when stimulated [162], are more efficient at lytic granule loading, and have a high per-cell killing capacity [163]. Some studies have found restoration of CD8+ T cell polyfunctionality by ART, suggesting that polyfunctionality is a consequence rather than cause of low viremia [164, 165]. However, these studies measured polyfunctionality in response to antigen stimulation and did not compare to LTNPs. This may account for the different result obtained in a recent study in which CD8+ T cell polyfunctionality in response to autologous HIV-1-infected CD4+ T cells was compared in patients on ART versus LTNPs with matched suppressed viral loads, where polyfunctionality was greater in LTNPs [160]. However, these authors argue that polyfunctionality is not likely to be an important determinant of immune control as polyfunctional cells form a small subset of the total HIV-specific CD8+ T cell response [160]. Proliferative and cytotoxic capacities of CD8+ T cells were superior in LTNPs when compared with patients on ART and these characteristics may contribute to immune control of HIV-1 [131, 160]. Interestingly, HIV-1 specific CD8+ as well as CD4+ T cell responses have been detected in HIV-1 exposed but seronegative individuals [146, 166].
The important role that the CD8+ T cells play in reducing viral load from a peak in early infection to a lower viral set point (Section 1.4.4.3.1) and the strong association of this set point with progression to AIDS (Section 1.6.1), as well as the CD8+ T cell depletion experiments in monkeys (Section 1.4.4.3.1), provide evidence that the CD8+ T cell responses are important in determining viral control and disease progression. However, perhaps the strongest evidence supporting this is the consistent, strong association of different HLA class I alleles, which present viral epitopes to activate CD8+ T cell mediated killing of infected cells (Section 1.4.4.3.1), with the rate of progression to AIDS [132, 167-
172]. A recent genome-wide association study on nearly 1,000 HIV-1 controllers revealed 313 SNPs associated with control, all of which were within the region coding for HLA concentrated in and around class I genes, suggesting it is the major factor involved in determining viral control [169].