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Impact of HLA-B*35 alleles on HIV disease outcome in Mexico and Central America

Valenzuela-Ponce H1, Ávila-Ríos S1, Garrido-Rodríguez D1, García-Téllez T1, Soto-Nava M1, Escamilla-Gómez T1, García-Morales C1, Cortés-Álvarez J1, Hernández R1, Murakami A1, Mejía-

Villatoro C2, Pascale J3, Porras G4, Quant C4, Lorenzana I5, Meza R5, Palou E5, Manzanero M6, Reyes-Terán G1 for the Mesoamerican HIV Project Group.

humberto.valenzuela@cieni.org.mx

1Instituto Nacional de Enfermedades Respiratorias, Mexico; 2Hospital Roosevelt, Guatemala; 3Instituto Conmemorativo Gorgas de la Salud, Panama; 4Hospital Metropolitano Vivian Pellas,

Nicaragua; 5HIV National Program, Honduras; 6Ministry of Health, Belize.

The authors declared no conflict of interest.

Background• It is well established that human leukocyte antigen (HLA) influences the rate

of HIV disease progression, the most consistent associations have been reported for HLA-B alleles.• HLA-B*35 has been associated with accelerated progression with the most

deleterious effects linked to a group of subtypes, HLA-B*35-PX.Allele Epitope anchor preference

P2 P9 (F-pocket)B*35:02 P XB*35:03 P XB*35:04 P XB*35:01 P YB*35:08 P Y

X= leucine, methionine or valine, but not tyrosine

B*35-PX

B*35-PY Reduced rate of disease progression

Rapid rate of disease progression

• 976 ART-naïve, HIV-1 clade B Mexican individuals.• No impact on viral load was observed in associations

with the B*35-PX/PY groups. • However, we observed differences in HIV disease

outcome associated with specific B*35 alleles.

Carrington M et al, Science 1999.Gao X et al, N Engl J Med 2001. Valenzuela-Ponce H et al. AIDS 2014

Cohort characteristics

Table 1. Clinical and demographic characteristicsCountry Mexico Central America All

N 1474 1400 2874

Age (median, [IQR]) 30 [24 – 38] 33 [26 – 42] 32 [25 - 40]

Female [N (%)] 309 (21.4%) 504 (36.0%) 813 (28.6%)

Log Plasma Viral Load (RNA copies/mL, median [IQR]) 4.68 [4.09 – 5.23] 4.60 [3.89 – 5.16] 4.64 [4.00 – 5.21]

CD4+ T cell counts (cells/μL, median [IQR]) 337 [135 – 555] 315 [124 – 504] 337 [131 – 541]

Mexico (n=1474) 21% ♀, 4.68, 337

Country (n) % (females)♀ , median pVL, median CD4 count

Belize (n=102) 49% ♀, 4.3, 470

Honduras (n=340) 42% ♀, 4.58, 300

Nicaragua (n=243) 20% ♀, 4.8, 316

Panama (n=297) 25% ♀, 4.34, 373

Guatemala (n=418) 44% ♀, 4.71, 225

37% of the individuals are B*35+

High diversity of relative unstudied B*35 alleles: 27 different alleles, 10 with N>10

PY PYPX PX

Diverse ranking of HLA-B*35 alleles according to the median pVL was observed

B*35:12 is a novel Amerindian HLA allele associated with higher pVL.

PY-

PX-

We observed B*35 additive detrimental effect and no homozygous disadvantage for specific B*35 alleles

Double postive individuals for other B*35 alleles were excluded from the analysis

No significant impact on median pVL was observed between HLA-B*35-PX/PY groups

AlleleResidue in HLA peptide

binding groove Epitope anchor preference

114 116 P2 P9B*35:02 N Y P XB*35:03 - F P XB*35:04 - - P XB*35:12 - - P X

3 other B*35 - F/Y P XB*35:01 D S P YB*35:08 - - P YB*35:14 - - P YB*35:16 - - P YB*35:17 - - P YB*35:20 - - P YB*35:43 - - P Y

13 other B*35 - - P Yx= leucine, methionine or valine, but not tyrosine

B*35-PX

Putative B*35-PX

B*35-PY

Putative B*35-PY

The magnitude of B*35 alleles effect in each region/country was not frequency-dependent

Summary

• B*35:01 (PY) , B*35:02 (PX) and B*35:12 (which is not considered disease-susceptible allele), were associated with higher pVL (p<0.05, q<0.1).• We observed B*35 additive detrimental effect and no homozygous

disadvantage for specific B*35 alleles.• Our data indicate that the classification of HLA-B*35 sybtypes into PX

and PY groups does not satisfactorily explain differences in median pVL.• These results challenge the B*35-PX/PY hyphothesis, indicanting that PY

alleles can be disease-susceptible and also that differences exist in disease associations within the PX/PY grouping. • Also the previous observation that the negative effect of the B*35 allelic

group is due to PX alleles is not supported by these data.• We conclude that the detrimental effect of B*35 is unlikely to be related

exclusively to PX/PY grouping.

Acknowledgments

Funding : Mexican Government (Comisión de Equidad y Género de la H. Cámara de Diputados).National Council of Science and

Technology (CONACYT).

Gustavo Reyes TeránSantiago Ávila Ríos

CIENI Center for Research in Infectious Diseases, Mexico City

HIV-infected blood donors

Daniela GarridoSelma Alva

Maribel SotoTania EscamillaClaudia GarcíaThalía García

Jonathan CortésSilvia del ArenalCIENI students

Collaborators/HLA typing

Ramón HernándezEdna RodríguezMario Preciado

Carolina DemeneghiRaymundo González

Israel Molina

Clinical Lab

Zeidy ArenasSandra Zamora

Berenice Cancino

Administrative staff

Pablo CésarEstebán Paz

Informatics staff

CIENI medical team Akio Murakami

María Gómez-PalacioKarla Romero

Dra. Indiana Torres (Puebla) Dr. César Carrasco (Oaxaca) Dr. Jaime Andrade (Jalisco) Dra. Sara Aguirre (Jalisco) Dra. Lucero González (Jalisco) Dra. Beatriz Ramírez (Edo. México) Dr. David de los Santos (Guerrero) Dr. Juan Carlos Martínez (Guerrero) Dra. Adakatia Armenta S. (Guerrero) Dr. Samuel Wong González (Sonora)

Dra. Angélica Zimbrón (Baja California) Dr. Samuel Navarro (Baja California) Dra. Lucrecia Ceja (Nuevo León) Dra. Ma. Catalina Juárez U. (Nuevo León)

Dr. Gastón Coronel (Veracruz) Dr. Yolanda Chévez (Morelos) Dra. Adriana García (Morelos) Biol. Anselmo Hernández C. (Morelos) Dra. Margarita Aguilar Ruiz (Chiapas)

Epidemiology Project GroupPhysician from Mexican states:

Collaborators from Central AmericaDr. Mexía Villatoro C (Guatemala)

Dr. Pascale J (Panama)Dr. Porras G (Nicaragua)Dr. Quant C Nicaragua)

Dr. Lorenzana I (Honduras)Dr. Meza R (Honduras)

Palou E (Honduras)Manzanero M (Belize)