Impact of host genetics on HIV disease progression and treatment

Introduction Research into the effects of host genetics on HIV disease susceptibility and progression, and on the efficacy and toxicity of drug treatment, occupies a particular position in the landscape of HIV research. On the one hand, an increased understanding of the role played by host genetic factors in determining the response to HIV infection (for a review see [1]) will undoubtedly contribute to our understanding of the nature of the disease process, and will ultimately assist the development of therapeutic strategies – such as vaccines – that can augment the genetically determined host immune response to HIV infection. In a limited number of cases a favourable host genetic profile will provide protection from HIV infection, or will confer ‘long-term non-progressor’ status following infection, allowing durable control of HIV-associated disease progression without the requirement for drug therapy. On the other hand, the relevance of these genetic factors to the routine clinical management of HIV-infected patients is often perceived as being marginal compared with the cost and difficulty associated with undertaking genetic testing, so that the assessment of host genetic factors is not incorporated into standard guidelines for HIV management [2,3]. Moreover, whilst genetic factors may significantly alter the rate of disease progression at an individual level, clinical decisions are currently based on defined endpoints such as CD4 T-cell number, HIV viral load, rate of CD4 T-cell decline and the clinical expression of AIDS- defining illnesses, irrespective of the host factors that may determine these values [2,3]. Several reviews are available that enumerate those host genetic factors that have a demonstrable effect on the course of HIV infection, including a recent comprehensive assessment of this field of research [1]. Here we will attempt to provide a broad conceptual framework for considering the impact of host genetic diversity on HIV/AIDS; one that argues that host genetic variation is an important factor in the response to HIV for every infected individual, and within every infected population; not just for those few individuals who carry genetic variants that have powerful protective (or deleterious) effects on HIV disease progression [4]. This review incorporates an evolutionary perspective that recognizes the ongoing dynamic interplay between host and viral genetic diversity at the population level, providing the driving force for the selection of favourable host genetic profiles as well as for viral mutations that are best adapted to these host effects. We also present a clinical perspective that considers analogies between ‘endogenous’ antiviral effects conferred by a broad spectrum of host genetic factors, and the effects of drug therapy. This model provides for a broad conception of the role of host factors in determining the overall progression of HIV disease, both before and after the introduction of antiretroviral therapy (Fig. 1).Fig. 1.: Host and pathogen genetic effects act at multiple levels to modulate HIV disease progression over time.An evolutionary perspective: host–pathogen interactions at the genetic level One interesting by-line in the story of the human genome project has been that our DNA is littered with the remnants of previous encounters with retroviruses. It is estimated that approximately 8% of human genetic sequence is derived directly from retroviral elements, and that subsequent transposition and recombination events have amplified this proportion to above 40% [5]. Moreover, the more recent human endogenous retroviruses have been acquired in the period since human evolution diverged from our nearest primate ancestors [6]. We have therefore encountered retroviral pathogens throughout our evolutionary history, and these infectious agents are likely to have shaped the evolution of critical aspects of our immunological response to viral infection. Recent evidence points to the purifying pressure that may be exerted by pathogenic viruses on host genetic diversity, suggesting that the selection of a limited number of major histocompatibility complex (MHC) alleles able to direct a strong protective immunological response against both SIV and the closely related human lentivirus HIV-1 has been a feature of the successful adaptation made by chimpanzees to SIV [7]. Evolutionary history is punctuated by these bottleneck events in which diversity is sacrificed in order to ensure the survival of populations in the face of epidemic or endemic pathogens, and it is these events that are likely to have determined the non-random distribution of MHC variants in different ethnically and geographically separated groups [8–11]. It is also interesting to observe, however, that the incorporation of retroelements into the human genome creates sites of genetic instability that have contributed to large-scale genetic duplication and recombination events – including within the MHC region – thus producing quantum evolutionary changes and the development of new genetic loci critical for immune function [12]. If we consider populations both past and present with no access to effective treatment for HIV infection, the only ‘weapons’ available to combat the spread of HIV are host genetic diversity (at a given time) and host genetic adaptation (developing over generations under the selective pressure of endemic HIV infection). Given that HIV is capable of rapid genetic adaptation to the host immune response, producing multiple generations of virions every day, it would be anticipated that the pathogen has a marked advantage in this conflict. However, in the human host's favour, there is a remarkable degree of diversity in key regions of the genome that encode for proteins that shape the immune response, so that adaptation to one individual does not provide a particularly strong advantage when infection is passed on to the next host. It is this ‘strength in diversity’ that defines the host population's most significant natural advantage; one that needs to be exploited in the development of therapeutic strategies such as vaccines [13]. Can we extrapolate this evolutionary perspective to the present era in any useful way? After more than 20 years of epidemic HIV infection (i.e., approximately one human generation), it is probably too early to see if human HLA diversity is being affected by this selective pressure. However, this time scale is more than ample for the generation of viral diversity in response to the genetically encoded human immune system. In this context, the ability of autologous HIV to make the appropriate mutational adaptations to HLA-restricted immune response has been demonstrated at the population level, where it predicts pre-treatment viral load setpoint [14]. This capacity for adaptation may be determined by: (i) the genetic barrier to escape (i.e., the number of mutational steps required to induce escape at a specific viral amino acid residue); (ii) costs to viral replicative fitness associated with escape mutations; (iii) the breadth of the HLA-restricted immune response to viral antigens (i.e., the number of epitopes recognized by a specific HLA allele); and (iv) the residual cytotoxic T lymphocyte (CTL) response present following escape mutation (see Fig. 2). We can therefore see that there is a dynamic relationship between the host and the infecting virus that is played out at the (host) individual level, as the virus seeks to evade the immune responses of the host in which it finds itself. This also translates to the population level, as HIV is passed from one individual to another through a population. It is therefore worth bearing in mind when considering the impact of specific host genetic factors that HIV represents a constantly shifting target for the host immune response.Fig. 2.: Analogies between the effects of drug resistance mutations and CTL escape mutations on viral load. (a) In the presence of a selected antiretroviral drug [in this case, lamivudine (3TC)], there is a reduction of viral load associated with effective therapy (1.5 log10copies/ml) in this hypothetical scenario. The subsequent development of a M184V resistance mutation under the selective pressure provided by 3TC is associated with a rebound of viral load due to drug resistance. However, the increase in viral load is offset in this case by a reduction of viral fitness, and some residual effect of 3TC on the mutated virus, so that the viral load does not return to baseline levels while 3TC is continued (net loss, 1.2 log10copies/ml). (b) Similarly, the CTL response to HIV-1 associated with HLA-B7 results in a reduction of viral load of approximately 1.1 log10copies/ml. However, the development of a S162X CTL escape mutation within the HIV reverse transcriptase sequence is associated with loss of HLA-B7-specific immune recognition at this site, and an increase in viral load that is again offset by reduced viral fitness and residual effects of HLA-B7 on mutated virus.Host genetic factors and the natural history of HIV disease progression The host immune response to HIV infection is shaped to a large extent by an individual's repertoire of antigen recognition molecules encoded within the MHC on chromosome 6 [15,16]. This region of the human genome is characterized by intense polymorphism, with over 1600 individual alleles currently known at the major HLA loci (Class I, HLA-A, HLA-B, HLA-C; Class II, HLA-DR). Hence, the inheritance of HLA alleles as well as polymorphic immunoregulatory genes within the central MHC region that are in strong linkage disequilibrium with them (e.g., cytokines such as tumour necrosis factor-α, chaperone proteins such as heat shock proteins), profoundly influences the capacity to recognize and destroy pathogens that have managed to breach the defences provided by protective mucosal barriers and innate immune responses [17]. The adaptive immune response also uses auxiliary systems of antigen recognition that are also highly polymorphic, such as the killer inhibitory receptor (KIR) gene cluster on chromosome 19 [18–21] which is involved in modulating immune responses through recognition of ‘missing self’ (identifying the absence of Class I MHC surface expression) as well as of specific ligand epitopes present on HLA-C and HLA-B alleles [18–21]. Polymorphic variation in chemokine receptor expression is also an important source of host defence against HIV [1], which is to some degree countered by the virus’ ability to utilize alternative coreceptors for cellular entry. Finally, there are a number of novel mechanisms used by the human host to neutralize the metabolic and transcriptional machinery employed by HIV for ongoing replication, which may be exemplified by the ability of the APOBEC3G gene product to induce hypermutation in the HIV gene sequence by interfering with pyrimidine nucleotide metabolism [22–24]. These non-antigen specific mechanisms are not subject to as much genetic polymorphism, and have in general provoked HIV to ‘solve’ the problems they pose (for example, the ability of the Vif regulatory protein to counter the antiviral effects of the APOBEC3G product [24–26]). Impact of MHC alleles and haplotypes on HIV disease progression Given that the immune response to viral antigens mediated by cytotoxic CD8 T cells is dependent on the presence of Class I MHC molecules (e.g., HLA-A and HLA-B), and that the recognition of peptide motifs by this system is highly specific for a given HLA allele, it is perhaps not surprising that the inheritance of certain Class I alleles has been associated with significantly more (or in some cases, less) effective immunological control of HIV infection compared with others [1,27]. A number of studies have identified effects of HLA alleles that are favourable in some cases (e.g., HLA-B57, HLA-B27) and unfavourable in others (e.g., HLA-B35 and HLA-B22 subtypes) [1,27–36], and have demonstrated that the combined effects of HLA alleles are predictive of long-term non-progressor status [35] and viral load set-point in the pre-treatment phase [30–32]. HLA-B18 has also been found to predict slower progression of HIV disease [31], and has also been linked to protection from acquiring HIV infection in two studies involving multiply exposed sex workers in Thailand [37] and Kenya [38]. As previously mentioned, these dominant allelic associations represent extreme examples of the dynamic relationship between HLA-restricted antigen recognition and the capacity for HIV to evade immune surveillance through mutation [14]. At one end of this spectrum are the powerful protective alleles such as HLA-B57 and whilst at the other end of the spectrum are alleles that may recognize epitopes with few to successful viral escape In case, it is the effect on viral load setpoint that is for genetic associations with disease As in Fig. the factors above that determine the antiviral efficacy of specific HLA alleles are to those determining antiretroviral drug Hence, that are to who HIV therapy may also be to the that are by HLA HIV disease progression at multiple levels In certain cases, the of HLA alleles on disease progression to a direct effect on HIV viral load (Fig. example, individuals who carry as well as other genetic within the MHC region that are linked to this the a more rapid CD4 T-cell decline particularly early in the course of disease to CD4 Fig. genetic of this has some on the CD4 T effect of this that this is associated with present within the central MHC than with [17]. Hence, it is that immunoregulatory gene encoded in this region determine the of CD4 T-cell in response to a given HIV This is by that a of with the associated MHC is associated with increased susceptibility to CD4 T-cell of HLA alleles on HIV disease progression may associations with linked genes within the MHC are provided of MHC haplotypes and associations with HIV disease progression, that HLA alleles and linked immunoregulatory genes within a MHC may have or effects on overall progression of tumour necrosis heat shock the direct of HIV infection (i.e., HIV viral load and CD4 T-cell genetic factors also to modulate susceptibility to by example, of has been associated with in both of the disease as well as in HIV-associated with in not whilst of the MHC is protective In the case of the MHC that these that individuals this more rapid CD4 T-cell decline and are at increased of at the at of to complex infection has also been linked to Class MHC in this case to the closely linked and alleles previously associated with of and in populations where these are disease associated with responses to pathogens following the introduction of antiretroviral therapy have also been associated with HLA with significant associations between the MHC and These strong genetic factors that susceptibility to specific is not a product of the of is also by the genetically determined immune response to the again suggesting that to is a that a broad of HLA alleles in the of MHC haplotypes may have complex associations with progression, as in Fig. Impact of chemokine receptor The effect of a in the receptor gene present in of and the significant protection against HIV-1 infection by at this allele, represents the between a host genetic factor and HIV disease progression in this genetic may have in populations under selective pressure provided by epidemic viral pathogens such as or of the of the chemokine receptor and the role of chemokine such as and in modulating chemokine receptor it has that in these genetic systems the of effects of chemokine receptor variation a model with as a important This has been and the of genetic variation in these systems has been in a large that also points out that effects of these host genetic factors on to the population Hence, the overall impact of chemokine receptor and chemokine receptor ligand may be in a to the MHC in that genetic variation is to the response to HIV-1 infection in most if not whilst dominant effects on disease progression (e.g., are The impact of chemokine receptor may also provide some the nature of host genetic effects on disease the dominant genetic effect of the receptor mutation can provide a significant barrier to successful HIV infection at an individual level, providing significant associations with disease progression and long-term non-progressor status However, the predictive of on disease progression to be dependent (i) disease with evidence for early effects that are as of HIV infection and (ii) presence of other host genetic factors, particularly that with to determine or status This is not to the impact of the mutation or other protective chemokine receptor mutations that can disease progression to an extent that is [1], to these genetic factors within an overall of selective pressure in individuals (Fig. example, is not in to confer non-progressor status is of the most protective HLA allele, However, of these host genetic factors to contribute to a more defined selective pressure provided by multiple genetically determined factors (Fig. In the case of chemokine receptor gene by providing another source of selective pressure this case, against the of viral these host genetic effects contribute to the overall immunological drug pressure against which HIV to viral The mutation may also augment the and of responses to HIV therapy with an ongoing to overall control treatment (Fig. this has not been selective act on In this context, effects of selective pressure from multiple may contribute to overall ability to control viral load and HIV-1 disease progression, in the presence of antiretroviral drug of mutation on response to antiretroviral therapy in the HIV In this of profiles of viral response antiretroviral presence of the mutation associated with an response to antiretroviral therapy early in the treatment course and over the subsequent It is that the baseline viral load of the than the and that after for baseline viral load the in response to treatment between the groups no significant These that the effect of on levels of to have an impact antiretroviral with the provided in Fig. role of and haplotypes The complex on chromosome 19 is a highly polymorphic region of the genome which that are on natural killer of the of this region is and the natural for a number of gene However, interactions between killer and may and may also immune responses on the gene involved [18–21]. The of the complex in modulating HIV disease progression has been a subject of in recent example, a known recognition that is to a number of HLA-B alleles has been associated with slower HIV disease progression with suggesting that the of the and a specific may this However, strong linkage disequilibrium within the complex it to effects to individual genes within a In recent studies we have identified associations between rapid CD4 T-cell decline and a that and a of alleles These that the effect of on HIV disease progression may the susceptibility of CD4 T cells to than viral load the ability of immune cells to recognize and destroy HIV-infected CD4 T cells through recognition of both (e.g., epitopes on HLA-C and HLA-B and (e.g., reduced Class I MHC expression – by regulatory viral proteins such as In this context, the genetically determined between inhibitory and alleles may an important role in the immunological response, with the inheritance of HLA alleles with which alleles Host genetic factors and the response to HIV therapy Here the major of research has been on associations between drug and HLA This has in the case of where two studies have demonstrated strong associations between and susceptibility to this The predictive of genetic may be with the incorporation of a central MHC within the heat shock protein gene as well as which in one increased the predictive of to and the predictive to This is one of research into host genetic effects that may have direct for clinical as the of this through genetic may significantly the of associated associated with the of It is also that susceptibility to – as with or without – is also conferred by genetic factors, as this is to in that individuals after patients for The protective effect of CD4 T-cell in the case of however, that a genetic is more likely to Class MHC alleles such as as is the case for most of the of associations that has not much is the for HLA alleles to the efficacy of drug therapy. This from the that mutations selected by drug therapy may also be sites where selective pressure is provided by HLA the resistance mutations associated with specific antiretroviral are from escape mutations interactions may as the selective pressure of drug therapy provides a new for This may (i) the generation of novel epitopes for HLA-restricted immune as has been demonstrated for the M184V reverse transcriptase mutation which can act as a for and (ii) (or of the capacity for escape mutations to at the of a drug resistance or at more sites through effects on of peptide example, a resistance mutation that within a to of immune recognition at this site, so that the mutation as a and a CTL escape in individuals is required in this it is that of drug resistance mutations associated with certain HLA alleles may to be strong in some cases to the of antiretroviral in the host and drug antiviral clinical of host genetic At a level, it may be that drug therapy for HIV is more effective when there is also a from the host immune response the of viral load. this has been provided by studies that CTL responses to HIV HIV treatment particularly in the presence of treatment associated with and that this immune response to the response to therapy the of CTL responses therapy is by those to treatment an that may viral load at baseline and early in the course of treatment with is associated with and of HIV-associated It may therefore be to the to host genetic effects that is to of antiretroviral therapy. the level of in the pre-treatment provides a of the overall selective pressure provided by host genetic factors, and the degree to which the autologous virus has been able to to this host immune individuals with residual immunological control of it may be that the viral load be with CD4 T-cell when when to antiretroviral and which to therapy the viral load is (i.e., HIV is likely to a on the efficacy of drug therapy to control so that effective therapy is in these On the other hand, treatment while control is present may for long-term by with antiretroviral therapy to combat HIV (Fig. the of endogenous antiviral factors for as as may also have particular in such as the central system that may limited from antiretroviral treatment It is that our conception of host genetic factors as of HIV disease progression needs to those few examples where allelic variation at a genetic a significant or to see that genetic variation at multiple levels to modulate disease progression for individual and that genetically determined factors in important in infected individuals to modulate the immunological response to HIV infection, and that this host response influences the evolution and diversity of the viral for more powerful to both the immunological and aspects of HIV disease at the population the important of host factors in HIV infection throughout the course of the disease – including the treatment phase – may also for to long-term HIV This can be in a number of a research an understanding of the complex and dynamic nature of host–pathogen interactions can shape the development of appropriate research example, to as a may effects susceptibility to HIV infection following HIV viral load rate of CD4 T-cell and susceptibility to specific these as and however, may on the and to for the most and of such is in a after in HIV where a of dynamic and these interactions at the individual level out at the population level, is for In this the provided by the of our host genetic diversity can be exploited to the problems associated with HIV a that may be by a to the can some of the of the and of the some of the of the of the