HIV

Assuming no treatment is taken, there are three phases in the progression of HIV infection:²

• Acute — usually occurs about 3 weeks post-exposure. During this phase, the virus replicates rapidly in CD4 T-cells, which is indicated by high viral load and high rate of CD4 T-cell destruction. This is when the host is the most infectious.
  
• Chronic — also known as clinical latency or asymptomatic HIV infection, the chronic phase is the second stage of infection. Viral replication is low and without treatment, those infected will progress to AIDS within 10+ years.
  
• AIDS — at this point, the virus has tremendously damaged the immune system and the host can no longer fight opportunistic infections.

Antibody tests are the most widely used diagnostic tests to detect HIV infection. It can take about 28 days post-exposure (window period) for HIV-specific antibodies to be detected. Nucleic acid tests (NAT) help determine the viral load in patients. The 2015 World Health Organization (WHO) “Clinical Guidelines: HIV Diagnosis” provides diagnostic test recommendations for different patient groups.⁴

HIV-mediated CD4+ T-cell depletion is believed to occur through several stages—(i) enhanced T-cell production upon infection, (ii) accelerated destruction of T-cells through immune responses, (iii) accelerated T-cell production as a response to T-cell depletion through cytokine signaling in the lymph nodes, (iv) accelerated viral replication resulting in the destruction of progenitor cells in the bone marrow, thymus and peripheral lymphoid systems.⁶ 

Flow cytometry is a standard technique used for determining CD4 counts as it provides accuracy, precision and reproducibility. Flow cytometry also provides high-throughput capabilities. Both percentage CD4+ T-lymphocytes among lymphocytes and absolute lymphocyte counts can be determined using flow cytometry. Dual-platform approaches for determining CD4 counts use a flow cytometer for generating percentage CD4+ T-lymphocytes and a hematological analyzer for enumerating absolute lymphocyte counts. Single-platform approaches determine CD4 counts without using a hematological analyzer by either directly counting the number of CD4+ T-lymphocytes in a given volume of blood by CD45 gating³ or by adding microbeads to a known volume of CD4-stained blood samples.⁴ Determining percentages or counts of CD3+CD4+ lymphocytes can be useful in monitoring HIV-infected individuals.⁵ Individuals with HIV typically exhibit a steady decrease of CD3+CD4+ lymphocyte counts as the infection progresses.⁶ At the final stages of infection, CD4 counts go below 200 CD4/µL³, resulting in severe immunodeficiency. ⁷

Using adoptive transfer of costimulated CD4+ T-cells for reconstituting CD4+ helper T-cell activity has been demonstrated to be a possible method to augment natural immunity to HIV-1 infection.⁸ HIV-mediated immunosuppression could also result in patients becoming more prone to frequent and severe infections. Opportunistic infections leading to diseases such as Pneumocystis pneumonia (PCP), toxoplasma encephalitis, cytomegalovirus (CMV) infections and tuberculosis are hallmarks of AIDS.⁹

Role of CD4 cell count testing in identifying and managing people with advanced HIV disease

The 2016 World Health Organization (WHO) “Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection” recommend starting ART regardless of CD4 T-cell count and that the use of CD4 T-cell count for ART response monitoring can be stopped in settings where routine viral load monitoring is available and people are stable on ART.¹⁰ However, CD4 T-cell count testing at baseline for all people living with HIV remains important.¹¹ Relying on clinical staging alone risks missing substantial numbers of people living with HIV with severe immune suppression. 

1. Bouteloup V, Sabin C, Mocroft A, et al. Reference curves for CD4 T-cell count response to combination antiretroviral therapy in HIV-1-infected treatment-naïve patients. HIV Med. 2017;18(1):33-44. doi:10.1111/hiv.12389
   
   
2. Sabin CA, Lundgren JD. The natural history of HIV infection. Curr Opin HIV AIDS. 2013;8(4):311-317. doi:10.1097/COH.0b013e328361fa66
   
   
3. Center for Disease Control and Prevention. Guidelines for performing single-platform absolute CD4+ T-cell determinations with CD45 gating for persons infected with human immunodeficiency virus. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5202a1.htm. Accessed October 4,2020.
   
   
4. Pattanapanyasat K. Immune status monitoring of HIV/AIDS patients in resource-limited settings: a review with an emphasis on CD4+ T-lymphocyte determination. Asian Pac J Allergy Immunol. 2012;30(1):11-25.
   
   
5. Giorgi JV, Hultin LE. Lymphocyte subset alterations and immunophenotyping by flow cytometry in HIV disease. Clin Immunol Newslett. 1990;10(4):55-61. doi: 10.1016/0197-1859(90)90024-3
   
   
6. Landay A, Ohlsson-Wilhelm B, Giorgi JV. Application of flow cytometry to the study of HIV infection. AIDS. 1990;4(6):479-497. doi: 10.1097/00002030-199006000-00001
   
   
7. Streicher HZ, Reitz MS Jr, Gallo RC. Human immunodeficiency viruses. In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. New York: Churchill Livingstone; 2000.
   
   
8. Levine BL, Bernstein WB, Aronson NE, et al. Adoptive transfer of costimulated CD4(+) T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection. Nat Med. 2002;8(1):47-53. doi: 10.1038/nm0102-47
   
   
9. National Institutes of Health. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/introduction?view=full Accessed October 4,2020.
   
   
10. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach – second edition. https://www.who.int/hiv/pub/arv/arv-2016/en. Published Jume 2016. Accessed September 23, 2020.
    
    
11. Ford N, Meintjes G, Vitoria M, Greene G, Chiller T. The evolving role of CD4 cell counts in HIV care. Curr Opin HIV AIDS. 2017;12(2):123-128. doi: 10.1097/COH.0000000000000348