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Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection.

Altfeld M, Rosenberg ES, Shankarappa R, Mukherjee JS, Hecht FM, Eldridge RL, Addo MM, Poon SH, Phillips MN, Robbins GK, Sax PE, Boswell S, Kahn JO, Brander C, Goulder PJ, Levy JA, Mullins JI, Walker BD - J. Exp. Med. (2001)

Bottom Line: The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy.We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population.Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses.

View Article: PubMed Central - PubMed

Affiliation: Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA.

ABSTRACT
Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

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Viral diversification using the HMA focused on the env C2-V5 region: diversification of the HIV-1 env C2-V5 region is shown for persons with treated acute HIV-1 infection (preseroconversion [pre-SC]), persons treated postseroconversion, but within 180 d of infection (post-SC) and persons first treated in the chronic phase of infection (chronic) in A. B shows the RD measured by HMA for the seven individuals of each group, for whom sufficient amounts of proviral DNA was isolated to perform analysis (1, AC16; 2, AC01; 3, AC03, 4, AC04, 5, AC09; 6, AC13; 7, AC22; 8, AC14; 9, AC10; 10, AC25; 11, AC21; 12, AC29; 13, OP286; 14, OP314; 15, 6001; 16, 6002; 17, 6003; 18, 6006; 19, 6007; 20, 6009; and 21, 6010).
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Figure 4: Viral diversification using the HMA focused on the env C2-V5 region: diversification of the HIV-1 env C2-V5 region is shown for persons with treated acute HIV-1 infection (preseroconversion [pre-SC]), persons treated postseroconversion, but within 180 d of infection (post-SC) and persons first treated in the chronic phase of infection (chronic) in A. B shows the RD measured by HMA for the seven individuals of each group, for whom sufficient amounts of proviral DNA was isolated to perform analysis (1, AC16; 2, AC01; 3, AC03, 4, AC04, 5, AC09; 6, AC13; 7, AC22; 8, AC14; 9, AC10; 10, AC25; 11, AC21; 12, AC29; 13, OP286; 14, OP314; 15, 6001; 16, 6002; 17, 6003; 18, 6006; 19, 6007; 20, 6009; and 21, 6010).

Mentions: After effective treatment with HAART for 6–12 mo, samples of 37 from the 40 individuals were analyzed, and in 21 individuals (7 from each group) sufficient amounts of proviral DNA were isolated to perform heteroduplex analysis. HIV-1 envelope genes had very low levels of diversity in six of the seven individuals treated before HIV-1 seroconversion, all of whom were highly adherent to medication regimens (relative diversity [RD] = 2.7 ± 0.3; Fig. 4). The seventh individual in this group (AC22) had a higher level diversity (RD = 3.4), associated with poor adherence to his antiretroviral drug regimen, and several viral rebounds during the first year of treatment. However, HIV-1–specific CTL responses did not increase in magnitude or breadth during or after the period of poor adherence in this single individual (online supplemental Table S1). In contrast, the individuals treated within 180 d of HIV-1 infection or during chronic infection showed significantly higher diversity in the env gene of the virus (RD = 3.3 ± 0.5, P < 0.03 and 3.7 ± 0.5, P < 0.001, respectively; Fig. 4). Differences in viral diversity between the two latter groups did not reach statistical significance (P = 0.14). Taken together these data indicate that the generation of genetic variants of HIV-1 may be reduced by the very early initiation of antiretroviral treatment with effective suppression of viral replication.


Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection.

Altfeld M, Rosenberg ES, Shankarappa R, Mukherjee JS, Hecht FM, Eldridge RL, Addo MM, Poon SH, Phillips MN, Robbins GK, Sax PE, Boswell S, Kahn JO, Brander C, Goulder PJ, Levy JA, Mullins JI, Walker BD - J. Exp. Med. (2001)

Viral diversification using the HMA focused on the env C2-V5 region: diversification of the HIV-1 env C2-V5 region is shown for persons with treated acute HIV-1 infection (preseroconversion [pre-SC]), persons treated postseroconversion, but within 180 d of infection (post-SC) and persons first treated in the chronic phase of infection (chronic) in A. B shows the RD measured by HMA for the seven individuals of each group, for whom sufficient amounts of proviral DNA was isolated to perform analysis (1, AC16; 2, AC01; 3, AC03, 4, AC04, 5, AC09; 6, AC13; 7, AC22; 8, AC14; 9, AC10; 10, AC25; 11, AC21; 12, AC29; 13, OP286; 14, OP314; 15, 6001; 16, 6002; 17, 6003; 18, 6006; 19, 6007; 20, 6009; and 21, 6010).
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Figure 4: Viral diversification using the HMA focused on the env C2-V5 region: diversification of the HIV-1 env C2-V5 region is shown for persons with treated acute HIV-1 infection (preseroconversion [pre-SC]), persons treated postseroconversion, but within 180 d of infection (post-SC) and persons first treated in the chronic phase of infection (chronic) in A. B shows the RD measured by HMA for the seven individuals of each group, for whom sufficient amounts of proviral DNA was isolated to perform analysis (1, AC16; 2, AC01; 3, AC03, 4, AC04, 5, AC09; 6, AC13; 7, AC22; 8, AC14; 9, AC10; 10, AC25; 11, AC21; 12, AC29; 13, OP286; 14, OP314; 15, 6001; 16, 6002; 17, 6003; 18, 6006; 19, 6007; 20, 6009; and 21, 6010).
Mentions: After effective treatment with HAART for 6–12 mo, samples of 37 from the 40 individuals were analyzed, and in 21 individuals (7 from each group) sufficient amounts of proviral DNA were isolated to perform heteroduplex analysis. HIV-1 envelope genes had very low levels of diversity in six of the seven individuals treated before HIV-1 seroconversion, all of whom were highly adherent to medication regimens (relative diversity [RD] = 2.7 ± 0.3; Fig. 4). The seventh individual in this group (AC22) had a higher level diversity (RD = 3.4), associated with poor adherence to his antiretroviral drug regimen, and several viral rebounds during the first year of treatment. However, HIV-1–specific CTL responses did not increase in magnitude or breadth during or after the period of poor adherence in this single individual (online supplemental Table S1). In contrast, the individuals treated within 180 d of HIV-1 infection or during chronic infection showed significantly higher diversity in the env gene of the virus (RD = 3.3 ± 0.5, P < 0.03 and 3.7 ± 0.5, P < 0.001, respectively; Fig. 4). Differences in viral diversity between the two latter groups did not reach statistical significance (P = 0.14). Taken together these data indicate that the generation of genetic variants of HIV-1 may be reduced by the very early initiation of antiretroviral treatment with effective suppression of viral replication.

Bottom Line: The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy.We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population.Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses.

View Article: PubMed Central - PubMed

Affiliation: Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA.

ABSTRACT
Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

Show MeSH
Related in: MedlinePlus