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Long-Term Non-Progression and Broad HIV-1-Specific Proliferative T-Cell Responses.

Imami N, Westrop SJ, Grageda N, Herasimtschuk AA - Front Immunol (2013)

Bottom Line: Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs.Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control.The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Imperial College London London, UK.

ABSTRACT
Complex mechanisms underlying the maintenance of fully functional, proliferative, HIV-1-specific T-cell responses involve processes from early T-cell development through to the final stages of T-cell differentiation and antigen recognition. Virus-specific proliferative CD4 and CD8 T-cell responses, important for the control of infection, are observed in some HIV-1(+) patients during early stages of disease, and are maintained in long-term non-progressing subjects. In the vast majority of HIV-1(+) patients, full immune functionality is lost when proliferative HIV-1-specific T-cell responses undergo a variable progressive decline throughout the course of chronic infection. This appears irreparable despite administration of potent combination antiretroviral therapy, which to date is non-curative, necessitating life-long administration and the development of effective, novel, therapeutic interventions. While a sterilizing cure, involving clearance of virus from the host, remains a primary aim, a "functional cure" may be a more feasible goal with considerable impact on worldwide HIV-1 infection. Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs. Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control. This review describes novel concepts underlying full immune functionality in the context of HIV-1 infection, which may be utilized in future strategies designed to improve upon existing therapy. The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.

No MeSH data available.


Related in: MedlinePlus

Characteristic proliferative responses detected by 3H-thymidine incorporation in a lymphocyte proliferation assay. (A) Illustration of the characteristic presence of proliferative responses to recombinant (r) Tat, rRev, rNef, rp24 (Gag), and rgp120 (Env) HIV-1 proteins observed in a “True LTNP” with suppressed HIV-1 plasma load, and (B) a typical lack of such responses in a chronically infected patient (Westrop et al., 2009b). Normal CD4 T-cell range of 450–1650 cells/μl blood is marked with horizontal lines. The threshold for positivity, stimulation index ≥ 3, is also marked with a dashed horizontal line (inset graph).
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Figure 1: Characteristic proliferative responses detected by 3H-thymidine incorporation in a lymphocyte proliferation assay. (A) Illustration of the characteristic presence of proliferative responses to recombinant (r) Tat, rRev, rNef, rp24 (Gag), and rgp120 (Env) HIV-1 proteins observed in a “True LTNP” with suppressed HIV-1 plasma load, and (B) a typical lack of such responses in a chronically infected patient (Westrop et al., 2009b). Normal CD4 T-cell range of 450–1650 cells/μl blood is marked with horizontal lines. The threshold for positivity, stimulation index ≥ 3, is also marked with a dashed horizontal line (inset graph).

Mentions: We have previously reported that even a small increase in pVL may be indicative of forthcoming clinically relevant changes of disease state. An increase from 1,236 to 6,483 RNA copies/ml plasma led to a loss of HIV-1 Gag-specific proliferative responses, and a shift toward a type II cytokine profile as indicated by loss of IL-2 production and increase in IL-4 production, and subsequent disease progression (Imami et al., 2002). This increase in pVL and loss of CD4 proliferation has also been described to occur in elite controllers who subsequently progress (Dyer et al., 2008). Comparison between two HIV-1+ individuals both presenting with atypical HIV-1 disease progression and non-declining CD4 counts is shown in Figure 1. Substantial proliferation to a number of HIV-1 proteins is demonstrated in a non-progressing individual with suppressed pVL (Figure 1A). Lack of such a proliferative response is seen when viremia is above detection limit (Figure 1B), albeit considerably lower than the majority of chronically infected HIV-1+ individuals. It is debatable whether the pVL in such situations is the cause or effect of immunological changes, and although cART-treated individuals provide a control group for low pVL, and therefore lower antigenic stimulation, additional effects of cART do not enable resolution of the cause versus effect question, bringing into the equation virologic factors such as infection with less pathogenic virus and the role of viral fitness (Blankson, 2010).


Long-Term Non-Progression and Broad HIV-1-Specific Proliferative T-Cell Responses.

Imami N, Westrop SJ, Grageda N, Herasimtschuk AA - Front Immunol (2013)

Characteristic proliferative responses detected by 3H-thymidine incorporation in a lymphocyte proliferation assay. (A) Illustration of the characteristic presence of proliferative responses to recombinant (r) Tat, rRev, rNef, rp24 (Gag), and rgp120 (Env) HIV-1 proteins observed in a “True LTNP” with suppressed HIV-1 plasma load, and (B) a typical lack of such responses in a chronically infected patient (Westrop et al., 2009b). Normal CD4 T-cell range of 450–1650 cells/μl blood is marked with horizontal lines. The threshold for positivity, stimulation index ≥ 3, is also marked with a dashed horizontal line (inset graph).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585435&req=5

Figure 1: Characteristic proliferative responses detected by 3H-thymidine incorporation in a lymphocyte proliferation assay. (A) Illustration of the characteristic presence of proliferative responses to recombinant (r) Tat, rRev, rNef, rp24 (Gag), and rgp120 (Env) HIV-1 proteins observed in a “True LTNP” with suppressed HIV-1 plasma load, and (B) a typical lack of such responses in a chronically infected patient (Westrop et al., 2009b). Normal CD4 T-cell range of 450–1650 cells/μl blood is marked with horizontal lines. The threshold for positivity, stimulation index ≥ 3, is also marked with a dashed horizontal line (inset graph).
Mentions: We have previously reported that even a small increase in pVL may be indicative of forthcoming clinically relevant changes of disease state. An increase from 1,236 to 6,483 RNA copies/ml plasma led to a loss of HIV-1 Gag-specific proliferative responses, and a shift toward a type II cytokine profile as indicated by loss of IL-2 production and increase in IL-4 production, and subsequent disease progression (Imami et al., 2002). This increase in pVL and loss of CD4 proliferation has also been described to occur in elite controllers who subsequently progress (Dyer et al., 2008). Comparison between two HIV-1+ individuals both presenting with atypical HIV-1 disease progression and non-declining CD4 counts is shown in Figure 1. Substantial proliferation to a number of HIV-1 proteins is demonstrated in a non-progressing individual with suppressed pVL (Figure 1A). Lack of such a proliferative response is seen when viremia is above detection limit (Figure 1B), albeit considerably lower than the majority of chronically infected HIV-1+ individuals. It is debatable whether the pVL in such situations is the cause or effect of immunological changes, and although cART-treated individuals provide a control group for low pVL, and therefore lower antigenic stimulation, additional effects of cART do not enable resolution of the cause versus effect question, bringing into the equation virologic factors such as infection with less pathogenic virus and the role of viral fitness (Blankson, 2010).

Bottom Line: Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs.Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control.The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Imperial College London London, UK.

ABSTRACT
Complex mechanisms underlying the maintenance of fully functional, proliferative, HIV-1-specific T-cell responses involve processes from early T-cell development through to the final stages of T-cell differentiation and antigen recognition. Virus-specific proliferative CD4 and CD8 T-cell responses, important for the control of infection, are observed in some HIV-1(+) patients during early stages of disease, and are maintained in long-term non-progressing subjects. In the vast majority of HIV-1(+) patients, full immune functionality is lost when proliferative HIV-1-specific T-cell responses undergo a variable progressive decline throughout the course of chronic infection. This appears irreparable despite administration of potent combination antiretroviral therapy, which to date is non-curative, necessitating life-long administration and the development of effective, novel, therapeutic interventions. While a sterilizing cure, involving clearance of virus from the host, remains a primary aim, a "functional cure" may be a more feasible goal with considerable impact on worldwide HIV-1 infection. Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs. Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control. This review describes novel concepts underlying full immune functionality in the context of HIV-1 infection, which may be utilized in future strategies designed to improve upon existing therapy. The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.

No MeSH data available.


Related in: MedlinePlus