HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus

Abstract

Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development.

Humanes Immunschwächevirus (HIV)

“…Ein hoher Anteil der neutralisierenden Antikör-per ist gegen den V3-loop des gp120 gerichtet. Die Antikörper sind stammspezifisch und können die sich im Organismus eines Individuums ausbildenden Quasispezies von HIV dauerhaft nicht ausreichend eliminieren [25,77,78]. Unter dem Eliminationsdruck des Immunsystems werden Viren mit variablem V3-loop selektioniert.…”

Socioeconomic Impact of HIV/AIDS on Households under Free Antiretroviral Therapy in Preah Sihanouk Province, Cambodia

“…Neither HIV-1-specific antibodies nor CD4+ T cell responses were investigated in this case, but might have contributed to the lack of control. At the same time, a case of HIV-1 superinfection involving two subtype B strains was also reported [9]. The individual enrolled in a structured treatment interruption trial after the initial infection, and developed a strong and broad HIV-1-specific CD8+ T cell response over time.…”

“…While the neutralizing antibody response was found to be low, a cellular response of this magnitude and breath did not translate into protection against the second HIV-1 strain even though its sequence only differed by 12%. Thus, these and additional well-documented cases demonstrated that superinfection can occur in the context of limited HIV-1-specific cytotoxic T cell responses mostly directed against a single epitope [10,35], yet it is not prevented by the presence of broad responses to multiple epitopes [9,11,34,39].…”

“…At a time when HIV-1 dual infections had not been adequately documented, the existence of recombinant forms provided the strongest support for their occurrence, which represents an important mechanism to generate new divergent HIV-1 strains. For instance, at the time HIV-1 superinfection was first reported in humans in 2002 [9][10][11], 14 circulating recombinant forms (CRFs) had been described. Today, the Los Alamos database reports 58 HIV-1 CRFs and 1 HIV-2 CRF, and as more HIV-1 variants inevitably intermix in different parts of the world, the likelihood of generating new recombinant viruses increases [6].…”

“…Since then, multiple reported cases have described interclade [10,11,[23][24][25][26][27][28][29] as well as intraclade [9,[30][31][32][33][34][35] superinfections, but also triple superinfections [28,32,36], or superinfections involving substantially divergent strains belonging to the different HIV-1 and HIV-2 groups [37,38].…”