The Game of T-Cells
“Chronicling the Epic Battles Between the Immune System with HIV, Other Threats, and Sometimes Itself"

For Maesters – Scientists, Providers, and the Curious

WHICH HOUSE WILL YOU SERVE?

Blue Wolf with a 4 by the headOrange octopus with a sword in one hand and an 8 embedded within

Blue 4 Overlayed on a Red X4 fists with red virus inlayed

QUESTION A: What are the peer-reviewed publications that describe the association between low ratios and clinical outcomes in HIV infected patients?

ANSWER A:

  1. Gergen M, Hewitt A, Sanger CB, Striker R. Monitoring immune recovery on HIV therapy: critical, helpful, or waste of money in the current era? AIDS. 2024 Feb 2. doi: 10.1097/QAD.0000000000003850. PMID: 38310348.
  2. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of no-AIDS morbidity and mortality. Serrano-Villar S, Sainz T, Lee S A et al. PLoS Pathog. 2014 May 15;10(5):31004078

3. The CD4:CD8 ratio is associated with markers of age-associated disease in virally suppressed HIV-infected patients with immunological recovery. Serrano-Villar S, Moreno S, Fuentes-Ferrer M, et al . HIV Med 2014; 1:40-39.

4. Role of Normalized T-Cell Subsets in Predicting Comorbidities in a Large Cohort of Geriatric HIV-infected Patient. Calcagno A, Piconi S, Focà E, et al; GEPPO (GEriatric Patients living with HIV/AIDS: a Prospective Multidimensional cOhort) Study Group. J Acquir Immune Defic Syndr. 2017

5. Impact of inversion of the CD4/CD8 ratio on the natural history of HIV-1 infection. Margolick J B, Gange S J, Detels R, et al.  J Acquir Immune Defic Syndr. 2006 Aug 15;42(5):620-6.

6. Immune activation and inflammation in HIV-1 infection: causes and consequences. Appay V, Sauce D. J Pathol 2008;214:231-241

7. CD4/CD8 ratio: an emerging biomarker for HIV. Serrano-Villar S, Deeks S C. Lancet HIV. 2015 Mar;2(3) 76-

8. CD4/CD8 ratio as a predictor of the response ot HBV vaccination in HIV-positive patients: a prospective cohort study. F, Vargas JL, Jensen D, Sarmiento V, Acuna P et al. Vaccine. 2016 Apr 7;34(16):1889-95

9. CD4/CD8 ratio predicts yellow fever vaccine-induced antibody titers in virologically suppressed HIV-infected patients. Avelino-Silva V, Miyaji KT, Mathias A. J Acquir Immune Defic Syndr 2016. Feb 1;71(2):189-95.

10. Virologically suppressed patients with asymptomatic and symptomatic HIV associated neurocognitive disorders do not display the same pattern of immune activation. Vassallo M, Durant J, Lebrun-Frenay C, et al.  HIV Med 2015. Aug;16(8):431-40

11. Immunological and infectious risk factors for lung cancer in US veterans with HIV: a longitudinal cohort study. Sigel K, Wisnivesky J, Crothers K, et al. Lancet HIV. 2017 Feb; 4(2): e67-73

12. A low peripheral blood CD4/CD8 ratio is associated with pulmonary emphysema in HIV. Triplette M, Attia E F, Akgun K M et al.  PLoS One. 2017 Jan 25; 12(1): e0170857

13. CD8_ T-cells count in acute myocardial infarction in HIV diseae in a predominatly male cohort. Badejo O, Chang C, So-Armah K, et al.  Bio Med Research International Vol 2015 (Article 246870)

QUESTION B: What are the peer-reviewed publications that describe the association between low ratios and clinical outcomes in non-HIV infected patients?

ANSWER B:

1. An Immune Risk Phenotype, Cognitive Impairment, and Survival in Very Late Life: Impact of Allostatic Load in Swedish Octogenarian and Nonagenarian Humans. Wikby A, Ferguson F, Forsey R, et al.  J Gerontol A Biol Sci Med Sci 2005; 60 (5): 556-565. doi: 10.1093/gerona/60.5.556

2.The immune-risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20-100 years of age. Wikby A, Månsson IA, Johansson B, et al. Biogerontology. 2008; 9:299-308.

3.Survival in a population sample is predicted by proportions of lymphocyte subsets. Huppert FA, Pinto EM, Morgan K, Brayne C.  Mech Ageing Dev. 2003;124:449-451

QUESTION C: CD8 T cells also do good things. Why are you putting them in a bad light? And who is LittleFinger?

ANSWER C:

“ All models are wrong, but some are useful“ – Maester George E.P. Box

We are just trying to have fun and highlight the emerging data about the CD4/CD8 ratio’s importance.  CD8s may do some “good” things, but clinical data suggests the when CD8 cells outnumber CD4s too much bad stuff happens.  We welcome criticisms and suggestions (especially if you know who LittleFinger is) but please understand that things in GRR Martin’s books are slightly different than the show and things will be different here as well. (Sorry no pornography here).

QUESTION D: What is the peer-reviewed data that ratio recovery is associated with a low HIV reservoir?

ANSWER D: The strongest evidence comes from a recent paper by Taisheng Li in BMC Infectious Diseases, in which they compared the cell associated HIV DNA in patients on therapy between 2 different matched cohorts, one with very low levels and one with higher levels. A higher CD4/CD8 recovery at week 96 was the only factor they examined that was associated with the difference in reservoir size. Speculation about a relationship between ratio recovery and reservoir size though dates back almost 2 decades to a case report co authored by none other than Dr Anthony Fauci himself. At that time it was quite uncommon to see a patient with a recovered or normal ratio, while now it is more common.

  1. Yue, Y. and Taisheng Li et. al. A higher CD4/CD8 ratio correlates with an ultralow cell-associated HIV-1 DNA level in chronically infected patients on antiretroviral therapy: a case control study. BMC Infectious Diseases (2017) 17:771.

QUESTIONS E & F: How do we know the ratio changes with age and by sex chromosome? If male ratios are different than female ratios, why doesn’t my clinical lab give two different normal ranges like they do for hemoglobin?

ANSWERS E & F:

Good questions! Both human data (Ho PC, Tang GW, Fu KH, Fan Mc, Lawton JW.  Immunologic studies in patients with premature ovarian failure.  Obstet Gynecol. 1988 Apr; 71(4):622-6)   as well as mouse data (Shao MJ, Zhu YJ, Qiu YE, Hu M, He YQ.  Changes in the Level of Immunoglobulins and CD4/CD8 Ratio in Young and Aged Mice with Estradiol Deficiency.  Immunol Invest. 2017 Apr;46(3):305-313) demonstrate evidence that both age and sex can alter what is “normal”. That said, the overlap between males and females is extensive.  The best estimates we have seen is that the ratio in fertile women is only ~ 0.1 or so higher than the ratio in men.  This poor understanding of “normal” clearly has hampered the clinical use of CD4:CD8 ratios for anything other than as a HIV biomarker.

QUESTION G: Is there peer reviewed literature on abnormal CD4:CD8 T cell ratios in other diseases unrelated to HIV?

ANSWER G:

Not as much as we would like, but yes. Recently a concept that incorporates the ratio, Immune Resilience (IR) has been coined and grounded in large datasets. Briefly IR has 4 “grades”, with a healthy immune system being grade 1, and grade 2-4 getting progressively worse. Both grade 1 and 2 have ratios> 1.0, whereas grades 3 and 4 have ratios less than 1.0. We look forward to papers in nonHIV patients comparing a continuous variable scale CD4/CD8 ratio below say 1.2 with the 4 grade IR system and see which system is most accurate. For further reading on IR see ref #1.

      1. Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection. Ahuja et. al. Nature Communications. 14 2023.
      2. Alegria, GC, Gazeau, P, Hillion, S, Daien, CI, and Cornec, DYK, Clinic Rev Allerg Immunol May 2017 entitled “Could lymphocyte Profiling be Useful to diagnose Systemic Autoimmune Diseases?” CD4:CD8 ratios may become useful markers in cancer immunotherapy but this is speculative at this time.
      3. Li Y, Zeng Q, Ellis MK, Ziong T, Balen J, McManus DP. CD4+ T-cell counts, CD4+/CD8+ T-cell count ratios, and antibody levels in migrant fisherman infected with Schistosoma japonicum in the Dongting Lake, China. Am J Trop Med Hyg. 2006 Nov;75(5):910-3.
      4. Tancini G, Barri S, Rescaldani R, Fiorelli G, Vivani S, Lissoni P. Analysis of T helper and suppressor lymphocyte subsets in relation to the clinical state of solid neoplasms. Oncology 1990: 47(5): 381-4 (A low CD4/CD8 ratio is seen in metastaic cancer patients with compared to control groups)
      5. Kamen-Siegel L, Rodin J, Seligman ME, Dwyer J. Explanatory style and cell-mediated immunity in elderly men and women.  Health Psychol 1991;10(4):229-35. (Low ratios are seen in pessimistic people

Most current research articles:

 

HIV-DNA content in different CD4+ T-cell subsets correlates with CD4+ cell :  CD8+ cell ratio or length of efficient treatment.

Gibellini L1, Pecorini S, De Biasi S, Bianchini E, Digaetano M, Pinti M, Carnevale G, Borghi V, Guaraldi G, Mussini C, Cossarizza A, Nasi M.

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIVcontrollers.

Chereau F1, Madec Y2, Sabin C3, Obel N4, Ruiz-Mateos E5, Chrysos G6, Fidler S7, Lehmann C8, Zangerle R9, Wittkop L10, Reiss P11, Hamouda O12, Estrada Perez V13, Leal M5, Mocroft A3, Garcia De Olalla P14, Ammassari A15, D’Arminio Monforte A16, Mussini C17, Segura F18, Castagna A19, Cavassini M20, Grabar S21, Morlat P22, De Wit S23, Lambotte O24, Meyer L1; HIV Controllers Project Working Group for the Collaboration of Observational HIVEpidemiological Research Europe (COHERE) in EuroCOORD.

CD4:CD8 ratio comparison between cohorts of HIV-positive Asians and Caucasians upon commencement of antiretroviral therapy.

Petoumenos K1, Choi JY2, Hoy J3, Kiertiburanakul S4, Ng OT5,6, Boyd M1,7, Rajasuriar R8,9, Law M1; Australian HIV Observational Database; TREATAsia HIVObservational Database.

The Revival of an “Old” Marker: CD4/CD8 Ratio.

Bruno G1, Saracino A1, Monno L1, Angarano G1.

A Low Peripheral Blood CD4/CD8 Ratio Is Associated with Pulmonary Emphysema in HIV.

Triplette M1, Attia EF1, Akgün KM2,3, Soo Hoo GW4,5, Freiberg MS6, Butt AA7,8, Wongtrakool C9,10, Goetz MB4,5, Brown ST11,12, Graber CJ4,5, Huang L13, Crothers K1.