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Human Immunodeficiency Virus Type 1 Infection Despite Prior Immunization with a Recombinant Envelope Vaccine Regimen M

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Human Immunodeficiency Virus Type 1 Infection Despite Prior Immunization with a Recombinant Envelope Vaccine Regimen M Proc. Natl. Acad. Sci. USA Vol. 93, pp. 3972-3977, April 1996 Medical Sciences Human immunodeficiency virus type 1 infection despite prior immunization with a recombinant envelope vaccine regimen M. JULIANA MCELRATH*, LAWRENCE COREY*tS, PHILIP D. GREENBERG*§, THOMAS J. MATTHEWSI, DAVID C. MONTEFIORI¶, LEE ROWEN*, LEROY HOOD*§II, AND JAMES I. MULLINS*t Departments of *Medicine, tLaboratory Medicine, §Immunology, lMolecular Biotechnology, and tMicrobiology, University of Washington School of Medicine, Seattle, WA 98195; and IDepartment of Surgery, Duke University Medical Center, Durham, NC 27710 Contributed by Leroy Hood, November 6, 1995 ABSTRACT With efforts underway to develop a preven- MATERIALS AND METHODS virus 1 it tive human immunodeficiency type (HIV-1) vaccine, A 24-year-old HIV-1 seronegative, healthy Caucasian who remains unclear which immune responses are sufficient to never received a smallpox vaccine and who reported involve- protect against infection and whether prior HIV-1 immunity ment in a stable monogamous sexual relationship with an can alter the subsequent course of HIV-1 infection. We HIV-uninfected partner was recruited for the study. Over 4 investigated these issues in the context of a volunteer who years, the volunteer received 6 HIV-1 envelope vaccinations received six HIV-1LAI envelope immunizations and 10 weeks (5, 7, 11) as outlined in Table 1. Approximately 3 months (week thereafter acquired HIV-1 infection through a high-risk sex- 206) after the last vac-env booster, the volunteer had an ual exposure. In contrast to nonvaccinated acutely infected increased HIV-1 antibody by ELISA and new Gag antibodies individuals, anamnestic HIV-1-specific B- and T-cell re- by Western blot assay (Table 1). Three months later (week sponses appeared within 3 weeks in this individual, and 222), testing revealed a markedly reactive HIV-1 ELISA and neutralizing antibody preceded CD8+ cytotoxic responses. Western blot assay. Upon questioning retrospectively, the Despite an asymptomatic course and an initial low level of subject disclosed that the previously reported monogamous detectable infectious virus, a progressive CD4+ cell decline relationship had ended and during week 203 the subject had and dysfunction occurred within 2 years. Although vaccina- engaged in unprotected anal intercourse with a new partner of tion elicited immunity to HIV-1 envelope, which was recalled unknown HIV-1 serostatus. Analysis of stored frozen speci- upon HIV-1 exposure, it was insufficient to prevent infection mens revealed no detectable HIV-1 RNA in sera from weeks and subsequent immunodeficiency. 140, 164, 193, 197, and 201, but HIV-1 RNA was detected in serum from week 206 (Table 1). These data indicate that HIV-1 probably was acquired at approximately week 203, The progressive spread of human immunodeficiency virus coincident with the high risk exposure, which we have desig- (HIV) infection has made development of a preventive vaccine nated as week 0 of infection. a global health priority. The immune responses that correlate Individuals with early HIV-1 infection at the University of with protection from HIV infection or control of disease are Washington Center for AIDS Primary Infection Clinic served unknown. Presumably, a vaccine is more likely to be efficacious as the nonvaccinated infected control group. Immune re- if it is capable of eliciting HIV-specific broad neutralizing sponses in these individuals were determined from peripheral antibodies, CD8+ cytotoxic T lymphocytes (CTL), and T blood mononuclear cells (PBMC) at various times following helper responses (1). Several vaccine regimens have provided presumed or known date of seroconversion. protection in nonhuman primates against challenge with HIV Antibody and Cellular Immune Assays. HIV-1 antibody was or simian immunodeficiency virus (SIV) (2-4). These findings measured by EIA (Genetic Systems, Seattle) and by Western have led to human trials to evaluate a variety of HIV-1 blot (Epitope, Beaverton, OR). Neutralizing antibody assays candidate vaccines (5-11). were performed as described (10, 11). Titers represent the Since the initiation of HIV vaccine trials by the AIDS reciprocals of sera dilutions required to reduce infectious virus Vaccine Clinical Trails Network, some study participants have titer by one log or >90% in CEM cell lines (for HIV-1LAI and acquired HIV infection, all as a result of high risk behavior HIV-1MN) and in PBMC (for the first isolated autologous (12). This report provides a detailed analysis of HIV-1 infec- HIV-1). C'-ADE was measured in MT-2 cells (13) by p24 tion in a vaccinated volunteer from one of these studies and production and is expressed as the reciprocal of the last serum compares these responses with a group of nonvaccinated dilution to show enhancement (titer), the reciprocal serum received dilution producing the greatest enhancement (peak), and the individuals with early HIV infection. The volunteer magnitude of enhancement at the peak dilution, given as the six vaccinations, three with a live recombinant vaccinia virus fold-increase in p24 production over background (power). containing HIV-1LAI gp160 (vac-env) and three with a bacu- LP responses were measured in vitro to HIV-1 antigens lovirus-derived HIV-lLAI recombinant envelope protein (2-10 gLg/ml) including psoralen-treated, UV-inactivated pu- (rgpl60) (5, 7, 11). This immunization approach has shown rified HIV-1LAI (kindly provided by S.-L Hu, Bristol-Myers/ promise in the macaque model with SIV infection (3) and has Squibb), gpl60 (HIV-1LAI strain, kindly provided by Micro- been particularly effective at inducing both HIV-specific neu- GeneSys, Meriden, CT), and Env 2-3 (HIV-lsF2 strain, kindly tralizing antibody and T-cell responses (7, 8). While it remains provided by K. Steimer, Biocine, Emeryville, CA), as described unclear why the regimen failed to protect this volunteer, the analysis establishes a framework with which to explore future Abbreviations: HIV-1, human immunodeficiency virus type 1; CTL, cases of HIV infection in vaccinated volunteers participating cytotoxic T lymphocytes; SIV, simian immunodeficiency virus; vac- in expanded clinical trials. env, recombinant vaccinia containing HIV-1LAI gpl60; rgpl60, re- combinant HIV-lLAI gpl60; PBMC, peripheral blood mononuclear cells; C'-ADE, complement-mediated antibody-dependent enhance- The publication costs of this article were defrayed in part by page charge ment; LP, lymphoproliferative; S.I., stimulation index; E/T, effector- payment. This article must therefore be hereby marked "advertisement" in to-target ratio; CC, co-culture. accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 3972 Downloaded by guest on October 2, 2021 Medical Sciences: McElrath et al. Proc. Natl. Acad. Sci. USA 93 (1996) ^ I0 4 "ooO0Ir.- 00 r4eVn t" O E en 4 = ^ ^ t k ^ 0%u e ^ e Y 8 Z . oo0o , ,v ,\ 0C,,N, +.m , o I N 0 I "sO00 P all 00 - 0o "O _._^ 0 I a c 111+i + + + +++ ++++&+^0-S S ° -o r~ 000 0 0o t CD " CD'T 0 VVV00 o00 C VVV V V V7V-cVooO_O4jg 0 _ e cO1O Ei V V V v vv S a o o ii i+i+i++ ++0C00. VvO r Q V V V Vtt~- u-aeoo & h 4) 0 C v v W).e c I)00 I- W~~~~ 'uICo 0 '" ' 0c VrVYa cJo Ns o\0oCW -< 4 " - ^ V' kO CX g s»^ ^^ 1Es^ -cV O1 s^- O~ v v o wd!c *1 LLc~~~~~ V V 0 0 eq 00 (N ._ Coo rcr- Cgu8E a* r vVV/ v "', ' S.0 elI In 'll "IT I') ^^on xi % rrl Cu v v co tn i I) t) w) I) v) v) t) 'v 0 c*") Cv en U" V --- .) O0Cu C v v v V VV V V V > > 00 \O I zll01 I I I V 00=0 O0 " C4 00 - v 00 00 I NO 00N Cu~e~ _ ~ Cu_ II II ~~~~II v v v to ~ V 0O O \DC0 O O A O o o oo - o o T" - v v VV ISu + ++ + I ii~~~ It + ..) Cu Ce + + + ++ + + + + ~~1~ >-o-o- .i. NF oo t - m ) 'O I t.-: rsi »-^ 14t cj t tr 4,4) ECCu Cu 0, 0 o > C-_- "-r^ t o^o Oo0o00 em 0 NOmo .^ Rt * C .i c n 00 oo ' ~ ~~~~~~~~~~~~~~0aoo rO. -41 -o c: O N t Oe 0 0" C C"'- e,,,Nc,lcl 0,c,l-eO",l0%~ > <-i»r> BrI\5 s f Ot eO0 0\ OO ci lC 0-4t> O o I I "00 - - IY r- r- N . .. N . ..4 \ \ ^ ^^mm Downloaded by guest on October 2, 2021 3974 Medical Sciences: McElrath et al. Proc. Natl. Acad. Sci. USA 93 (1996) (5, 7). A stimulation index (S.I.) of -3 was considered positive infection, the counts declined to 255 cells/mm3 and remained for the HIV-1LAI antigen and -4.0 was considered positive for -300 cells/mm3 through week 116 after infection. gp160 and ENV 2-3 antigens. For analysis of CD8+ CTL, fresh At week 206, 3 weeks after infection, 53,400 copies/ml of PBMC were stimulated for two 1-week intervals with autolo- HIV RNA were detected in serum. Levels in plasma fell to gous HIV-1Ba-L-infected macrophages as described (14). Ef- < 10,000 copies/ml at 21 and 25 weeks after infection, and were fectors were tested for lysis of autologous Epstein-Barr virus- intermittently detectable between 39,800 and 82,100 copies/ml transformed B lymphoblastoid cell lines infected with recom- over the next 62 weeks. Attempts to isolate HIV-1 from PBMC binant vaccinia expressing either HIV-1LAI Env, Gag, or Pol were unsuccessful until 30 weeks after infection, and subse- and vaccinia wild-type control or pulsed with HIV-1LAI gp160 quent PBMC cultures were intermittently positive (Table 1).
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