Table 1:

Summary of noteworthy studies providing evidence of cytolytic and non-cytolytic antiviral activity of CD8+ T cells during HIV/SIV infection during different phases of infection, including treatment and natural control. Abbreviations: HIV: Human immunodeficiency virus; SIV: Simian immunodeficiency virus; PBMC: peripheral blood mononuclear cell; ART: Antiretroviral therapy; RM: Rhesus macaque; EC: Elite controller; CP: Chronic progressor; CTL: Cytotoxic T lymphocyte; CD: cluster of differentiation; IL: interleukin; IFN: interferon; TNF: tumor necrosis factor; CCL: chemokine (C-C motif) ligand; CCR: chemokine receptor; PD-1: programmed death-1; HLA: human leukocyte antigen; MIP: macrophage inflammatory protein ; CAF: CD8 antiviral factor.

Phase	Finding	Evidence	Reference
Acute infection	CD8 T cells are required for the initial control of HIV viremia.	Depletion of CD8+ lymphocytes from RM at the time of SIV infection resulted in abrogation of post peak decline.	[26, 175]
	After initial lag period, HIV-specific CD8+ T cells massively expand and differentiate at the time of peak viremia.	HIV-specific CD8+ T cells exhibit a delay in expansion and differentiation until peak viremia when compartment becomes fully expanded and differentiation in response to systemic proinflammatory cytokine burst, allowing for effective killing of productively-infected cells.	[176]
	The emergence of HIV-specific CD8+ T cells is associated with partial control of acute infection.	Increasing frequency of precursor CD8+ T cells specific for HIV-1 gag, pol, and env viral proteins using PBMC from patients experiencing acute HIV infection was correlated with partial resolution of peak viremia.	[24, 25]
	CD8+ T cells are capable of exerting significant selective pressure on the HIV viral genome.	Identification of the rapid appearance of specific escape mutations in HIV genome.	[29, 153]
	Acute HIV infection induces massive activation and expansion of the entire CD8+ T cell compartment	CD8+ T cell frequencies increase during the course of infection in HIV+ individuals and do not return to normal.	[177]
		Activation marker CD38 is up-regulated on Epstein Barr-, Cytomegalovirus- and influenza-specific CD8+ T cells during acute HIV infection, although activation was highest in HIV-specific cells.	[178]
		HIV-specific CD8+ T cells represent less than 10% of the total CD8+ T cell pool expanded during the acute infection.	[32]
		During the acute infection as high as 80%-90% of the entire CD8+ T cell compartment becomes activated.	[55]
	CD8+ T cell expansion can occur through antigen-independent mechanisms.	Microbial products systemically translocated across the gut epithelium contribute to the chronic activation of CD8+ T cells.	[22]
		Lipopolysaccharide and inactivated HIV activate monocyte-derived dendritic cells, which are capable of activating CD8+ T cells via transpresentation of IL-15. Therefore, proliferation and activation of the CD8+ T cell pool is initiated by cytokines, most notably IL-15.	[179]
	HIV-specific CD8+ T cells become exhausted during the acute infection and do not recover.	HIV–specific CD8+ T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication.	[73]
		HIV-specific CD8+ T cells provide a very early, robust, and highly activated effector response with immediate cytotoxic potential (as measured by perforin expression), but the ability is quickly lost after resolution of peak viremia.	[49]
		After full differentiation and expansion, HIV-specific CD8+ T cells reach a hyperproliferation state that is “too strong for too long” and push them to terminally differentiated effector cells that contributes to exhaustion.	[176]
Chronic infection	CD8+ T cells contribute to control during chronic HIV infection.	CD8+ T cell depletion during chronic infection results in an increase in viremia that is not controlled until reconstitution of depleted cells.	[50-52]
	Expanded CD8+ T cell population in chronically HIV-infected patients shows symptoms of immunosenescence.	HIV-specific CD8+ T cells lack of proliferative capability in response to cognate antigen (ex vivo), which could not be overcome by exogenous IL-2 or IL-15. These cells were associated with expression of CD57.	[46]
		Ex vivo analysis of virus-specific CD8 T cells shows that HIV disease progression correlates with increased proportions of highly differentiated CD8+ T cells, which exhibit characteristics of replicative senescence: CD57 expression, inability to proliferate in response to antigen, and shortened telomeres.	[55]
	The HIV-specific CD8+ T cell compartment has a skewed differentiation pattern towards effector memory during chronic infection.	70% of HIV-specific CD8+ T cells were found to be CD45RA-CCR7-, in contrast to cytomegalovirus-specific CD8+ T cells where only 40% are CD45RA-CCR7-.	[180]
	Expression of exhaustion markers on HIV-specific CD8+ T cells continues during chronic infection and contributes to disease progression.	Persistent antigen during chronic HIV infection contributes to the impairment of HIV-specific CD8+ T cells. HIV-specific CD8+ T cells show significant upregulation of PD-1. Expression correlates positively with impaired function, viral load and inversely with CD4+ T cell count.	[41, 42, 44]
		TIM-3 expression on CD8+ T cells correlates positively with viral load and inversely with CD4 counts during chronic HIV infection.	[140]
	PD-1 expression on HIV-specific CD8+ T cells is correlated with decreased survival, proliferation, and cytokine expression.	Ex vivo anti-PD-L1 treatment of CD8+ T cells from HIV+ donors led to changes in the ability of the cells to survive, expand, and secrete cytokines.	[42]
	HIV-specific CD8+ T cells exhibit reduced polyfunctionality during chronic infection.	HIV-specific CD8+ T cells from HIV+ donors exhibit decrease CD107, IFNγ, CCL4, IL-2, and TNFα expression after stimulation.	[40]
	HIV-specific CD8+ T cells exhibit impaired cytolytic function during chronic infection	Perforin expression was significantly lower in HIV-specific CD8+ T cells compared to CMV-specific CD8+ T cells of the same donor.	[57]
	CD8+ T cells secrete factors that are capable of suppressing replication of HIV through non-cytolytic mechanisms.	CD8+ T cells were found to release β-chemokines (CCL3, CCL4, and CCL5) with suppressive activities capable of blocking entry of M-tropic viruses.	[102, 112, 113]
		Replication of HIV in latently infected, resting CD4+ T cell reservoir is effectively suppressed in ex vivo coculture by autologous CD8+ T cells in EC and ART-treated patients but not ART-naïve patients.	[114]
		Identification of the characterization of CD8+ T cells with a MIP-1β expression profile as a correlate of virus control and inhibition.	[115, 116]
		CAF suppresses LTR-mediated HIV gene expression in CD4+ T cells.	[124]
		CD8+ T cells suppress replication by inhibiting viral transcription and proviral gene expression].	[130-132]
		SIV-infected RM were initiated on ART in the absence or presence of CD8+ T cells. The rates of viral decay did not differ between the two groups, suggesting that CD8+ T cells do not decrease the lifespan of productively infected cells. Thus, the antiviral mechanism of CD8+ T cells may be non-cytolytic.	[133, 134]
Natural control	CD8+ T cells are important during the control of SIV viral replication during RM controller infection.	Depletion of CD8+ lymphocytes in SIV controller RM resulted in a transient and significant increase in viremia and control was reestablished with the reconstitution of CD8+ T cells.	[66]
	HIV-specific CD8+ T cells from EC maintain high polyfunctionality.	HIV-specific CD8+ showed increase function via expression of 5 functional markers: CD107 (degranulation), IFNγ, CCL4, IL-2, and TNFα.	[40]
	HIV-specific CD8+ T cells from EC show better maintenance of cytolytic potential compared to CP.	HIV-specific CD8+ T cells of EC exhibit greater cytolytic capacity compared to CP. The strong ability of EC to kill HIV-infected CD4+ T cells was mediated by the delivery of granzyme B to target cells, an observation not congruent in CP.	[76]
		During chronic infection, cytolytic potential is lost rapidly in most HIV-infected individuals, such that only around 15% of HIV-specific CD8+ T cells express perforin, whereas around 40% express perforin in EC.	[75]
	HIV-specific CD8+ T cells from EC have a higher proliferative capacity as compared to CP.	High proliferative capacity of HIV-specific CD8+ T cells EC is coupled to increases in perforin expression with relative absence of these functions in CP.	[72]
	Host factors related to CD8+ T cells contribute to the control of HIV infection observed in EC.	CD8+ T cells restricted by certain protective alleles (HLA-B27 and -B57) can resist replicative defects, which permits expansion and antiviral effector activities.	[74]
	HIV-specific CD8+ T cells of EC have a higher functional recall memory than CP.	The expansion of CD8+ T cells producing IFNγ alone or in combination with IL-2 in response to gag peptides presented on monocyte-derived dendritic cells is limited in CP compared to EC. This was not observed by CD8+ cells in response to influenza, cytomegalovirus, and Epstein Barr virus.	[181]
	HIV-specific CD8+ T cells put selective pressure on the virus during EC infection.	Sequencing of plasma viremia of EC shows a discordance between the genotypes of the plasma virus and provirus. Specifically, HLA-B*57-restricted Gag epitopes were present in plasma virus but rare in provirus.	[67]
Treated infection	CD8+ T cells are required for the maintenance of viral suppression under ART.	Depletion of CD8+ lymphocytes from SIV+ RM during short-term ART results in a rebound of viremia.	[174]
	HIV-specific CD8+ T cells decline in peripheral blood after the initiation of ART	The longitudinal responses to 95 HLA class I-restricted HIV epitopes were measured using intracellular staining in HIV+ patients beginning ART. A rapid decline in HIV-specific CD8+ T cell response was observed upon initiation of ART. Discontinuation of ART resulted in a rapid increase in HIV-specific CD8+ T cells.	[149]
	Dysfunction of HIV-specific CD8+ T cells is decreased, but not restored during ART.	In a longitudinal study of HIV-infected patients, ART initiation resulted in some restoration of cytokine secretion, increase of IL-7Rα and CD28 expression, and a decline of PD-1 on HIV-specific CD8+ T cells.	[147]
		Defective HIV-specific CD8+ T cell polyfunctionality, proliferation, and cytotoxicity are not restored by ART	[182]
	ART does not resolve CD8+ T cell compartment elevation.	ART does not restore ongoing elevation of CD8 counts despite normalized CD4 count, resulting in a persistently low CD4:CD8 ratio even during virological control. This phenotype is correlated with markers of T cell activation and innate immune active, immunosenescence, and serious non-AIDS events and mortality.	[183]
		Early initiation of ART during HIV infection, not prolonged duration of ART, contributes to partial normalization of CD8+ T cell counts.	[150]
	ART is able to partially reverse the exhaustion of virus-specific CD8+ T cells observed during chronic HIV infection.	ART-initiation reverses expression of PD-1 on HIV-specific CD8+ T cells, reversing the functional impairment of these cells that had been caused by the constant presence of HIV antigen.	[145]
		HIV-specific CD8+ T cells from ART-treated patients expressed significantly lower levels of TIM-3 compared with untreated patients and TIM-3 expression was positively correlated with viral load.	[144]