Natural History- Trofile - Monogram Biosciences

Natural History

CCR5 Δ32 (delta 32) is a non-functional CCR5 receptor and is characterized by a deletion of 32 base pairs in the open reading frame. Individuals with CCR5 delta 32 have a perfectly normal phenotype except for a heightened risk of West Nile virus.

For reasons not fully understood at present, most cases of primary HIV-1 occur with the R5 virus.^5,6 This is even true if the source patient had evidence of CXCR4-utilizing virus (ie, dual/mixed virus and or X4 virus).^5,6

1% of Northern European Caucasians homozygous for the deletion (CCR5 absent)
15% of European Caucasians heterozygous for the deletion (CCR5 deficient [30% normal levels])¹⁷
Absence of CCR5 generally well tolerated
CCR5 delta 32 homozygotes are highly resistant to infection with R5 HIV-1

Wild Type

Susceptible to HIV

Heterozygotes

Susceptible to HIV
Progress more slowly

Δ32 CCR5 Homozygotes

Highly resistant to R5 HIV
No significant side effects

CCR5 Δ32 homozygote

Individuals who are CCR5 delta 32 homozygous do not express functional CCR5 chemokine receptors. These individuals have an outwardly normal phenotype and life expectancy apart from an increased susceptibility to West Nile virus. More importantly however was the fact that these individuals seem to be essentially immune to HIV infection. Recorded cases of individuals who are CCR5 delta 32 homozygous becoming infected with HIV are extremely rare and always involve CXCR4 using viruses. Individuals who are CCR5 delta 32 heterogous (one functional CCR5 gene) and acquire HIV infection, tend to have an attenuated course of disease.

de Roda Husman A-M, et al. Ann Intern Med. 1997;127:882-890.

Representative Trofile Patterns

During the early stage of HIV-1 infection (as determined in subtype B HIV-1 infections), the R5 virus predominates. Over 80% of individuals with early stage HIV-1 infection have R5 virus.^7,8 However, as HIV-1 disease progresses, the prevalence of CXCR4-utilizing viruses gradually increases.⁹ This shift is typically characterized by the emergence of dual-tropic virus (a virus that can utilize both CCR5 and CXCR4 co-receptors) and not simply the emergence of a pure X4 virus. Pure X4 virus populations are rare and account for only 0.1% of the treatment naive population^7,8 and 3% to 4% of the treatment experienced group.^9,10,11 About 50% of people with HIV-1 that progress to AIDS demonstrate only R5 virus throughout the entire course of HIV-1 disease.

Coakley E, et al. Second International Workshop Targeting HIV Entry. 2006. #8.

Treatment Experienced Patients

HIV-1 individuals with stable HAART (highly active antiretroviral therapy) failure exhibit higher levels of dual/mixed virus than treatment naive individuals with the same CD4+ count. It is unclear at present whether the higher levels of CXCR4-utilizing viruses are driven by HAART therapy or reflective of the underlying degree of disease progression (Table 1).

Table 1. The prevalence of both R5 and X4 viruses in treatment naive and treatment experienced HIV-1 infected patients

STUDY	POPULATION	NO. PATIENTS	R5 VIRUS	DUAL/MIXED VIRUS	X4 VIRUS
Homer cohort⁷	Naive	979	82%	18%	<1%
Chelsea Cohort⁸	Naive	402	81%	18%	<1%
ACTG 5211⁹	Experienced	391	50%	46%	4%
MOTIVATE 1 & 2¹⁰	Experienced	2,560	56%	41%	3%